Process for producing avermectin derivative

ABSTRACT

According to the present invention, 22,23-dihydroavermectin B1a, which is useful as a medicine, a veterinary drug, and a pesticide, can be directly fermented and produced. This can obviate the need for the complicated and difficult conventional processes for purifying avermectin B1a at an industrial level and for chemically modifying avermectin B1a and can significantly decrease cost and time required in the industrial production of 22,34-dihydroavermectin B1a. The production of the formulation containing only 22,23-dihydroavermectin B1a, which is highly effective as a medicine, is also realized.

TECHNICAL FIELD

[0001] The present invention relates to a process for producing22,23-dihydroavermectin B1a or a derivative thereof, which is useful asa medicine, a substrate compound and a modified avermectin aglyconsynthase used in the production, and a gene encoding the enzyme.

BACKGROUND ART

[0002] A conventional process for producing 22,23-dihydroavermectin B1ainvolves a method comprising extracting an avermectin mixture withorganic solvents from various microorganisms producing a plurality ofavermectins, purifying avermectin B1 in the extract, and reducing thecarbon bond between the 22nd and 23rd positions of avermectin B1 withhydrogen in the presence of a catalytic amount of compounds (JapanesePublished Unexamined Patent Application No. 61198/79). A mixture of22,23-dihydroavermectin B1a and 22,23-dihydroavermectin B1b obtained bythe process, which is called 22,23-dihydroavermectin B1, is used as amedicine.

[0003] Avermectin is a polyketide compound which, as with otherpolyketide compounds, is biosynthesized through continuous condensationof lower fatty acids, reduction of a carbonyl group at β position of anelongated acyl group, dehydration, or enoyl reduction. These variousrepetitive synthetic processes of many polyketide compounds are carriedout by a polymeric and multifunctional enzyme complexes, each of whichhas a specific active site (domain) required for each catalyticactivity. A general reaction formula of polyketide biosynthesis isoutlined, for example in Ann. Rev. Gen., 24, 37 (1990) and Ann. Rev.Microbiol., 47, 875 (1993).

[0004] DNA encoding a polyketide synthase usually encodes all therequired activity sites for the synthesis of a polyketide backbone(aglycon), and contains modules, that is, repeating units involvingcondensation steps and modification steps following condensation.Depending on the genetic information existing in each module, theelongation or modification of an acyl group is determined. A polyketidesynthase specifically acts on a specific carboxylic acid constitutionalunit that is involved in each condensation step or acts on a site thatdefines the specific modifying function after condensation.

[0005] Regarding the biosynthetic mechanism of avermectin aglycon, ithas been reported that, as with other polyketide compounds, avermectinaglycon contains lower fatty acids, such as acetic acid and propionicacid as its components [J. Antibiot., 39, 541-549 (1986)], and apolyketide synthase constituted by modules is present inavermectin-producing bacteria [Gene, 115, 119-125 (1992), Ann. New YorkAcad. of Sci., 721, 123-132 (1994)]. DNA fragments involved in thebiosynthesis of avermectin (Japanese Published Unexamined PatentApplication No. 15391/91) or domain structures of some modules [Ann. NewYork Acad. Sci., 721, 123-132 (1994)] have been reported although thenucleotide sequence, which is the basis thereof, is not disclosed. Thatis, the existence of some modules in the avermectin aglycon synthase ismerely presumed while the structure of the entire synthase has not beenelucidated. The present inventors made an intensive investigation intoavermectin aglycon biosynthase genes, thereby precisely deducing thedomain structure of each module involved in the biosynthesis ofavermectin aglycon.

[0006] Among 22,23-dihydroavermectin B1 components,22,23-dihydroavermectin B1a is known as a highly effective medicine[Antimicrobial Agent and Chemotherapy, 15, 372-378 (1979) and JapanesePublished Examined Publication No. 54113/87]. Avermectin B1a, which is araw material for synthesizing 22,23-dihydroavermectin B1a, is obtainedby culturing avermectin B1a producing microorganisms and purifying itfrom the culture. Streptomyces avermitilis, which produces avermectin,produces 8 components of avermectins having analogous structures(Japanese published Examined Publication No. 17558/90). Among strainsselectively producing avermectin component which were mutated and bredfrom Streptomyces avermitilis, any strains which produce only avermectinB1a are not obtained. Accordingly, avermectin B1a should be isolatedfrom avermectins having analogous structures for the purpose ofproducing 22,23-dihydroavermectin B1a. However, since there areextraordinary similarities between avermectin structures, it is verydifficult to industrially isolate only avermectin B1a. For this reason,it is considered that a currently used 22,23-dihydroavermectinpreparation consists of dihydroavermectin B1a and dihydroavermectin B1b.The necessity of hydrogenation with a special catalyst afterpurification complicates the process for producing22,23-dihydroavermectin B1 and results in increased cost.

[0007] Accordingly, if only 22,23-dihydroavermectin B1a can be directlyproduced, all the problems involved in conventional industrialproduction can be solved and medicines containing only22,23-dihydroavermectin B1a, which has the highest antiparasiticactivity in its component, can be produced. A process for selectivelyand directly producing 22,23-dihydroavermectin B1a, however, is notknown yet.

DISCLOSURE OF THE INVENTION

[0008] The object of the present invention is to provide a process forselectively and directly producing only 22,23-dihydroavermectin B1a.

[0009] The present inventors have made an intensive investigation intostudies in order to attain the above object and, have found that22,23-dihydroavermectin B1a or a derivative thereof can be directlyproduced by modifying a gene encoding an avermectin aglycon synthase toobtain a modified enzyme and allowing a compound, which is a substrateof the modified enzyme, to act on a cell in which the modified geneshave been expressed. The present invention has been completed on thebasis of this result.

[0010] The present invention relates to the following (1) to (25).

[0011] (1) A modified avermectin aglycon synthase comprising at leastone domain with an eliminated or lowered activity, wherein the domain isselected from the group consisting of acyl carrier protein (ACP),β-ketoacyl ACP synthase (KS), acyltransferase (AT), β-ketoacyl ACPreductase (KR), dehydratase (DH), enoyl reductase (ER) and thioesterase(TE), which are involved in the synthesizing reaction of avermectinaglycon.

[0012] (2) The modified avermectin aglycon synthase according to (1)wherein the modified avermectin aglycon synthase is derived fromStreptomyces avermitilis.

[0013] (3) The modified avermectin aglycon synthase according to (1)above, wherein the domain with an eliminated or lowered activity isselected from the group consisting of ATs, ACPs, KS1, AT1, KR1, ACP1,KS2, DH2 and KR2.

[0014] (4) A modified avermectin aglycon synthase comprising an aminoacid sequence wherein one or more amino acid residues are deleted,substituted or added in the amino acid sequence of the avermectinaglycon synthase consisting of the amino acid sequences shown in SEQ IDNOs: 4, 5, 6 and 7, and having an activity for producing22,23-dihydroavermectin B1a or a derivative thereof when the modifiedavermectin aglycon synthase is contacted with an N-acetylcysteaminethioester compound.

[0015] (5) The modified avermectin aglycon synthase according to (4)above, which contains a polypeptide consisting of the amino acidsequence shown in SEQ ID NO: 8.

[0016] (6) The modified avermectin aglycon synthase according to (4)above, wherein the N-acetylcysteamine thioester compound is representedby formula (I):

[0017] wherein R¹ and R², which may be the same or different, representhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl or substitutedor unsubstituted heterocycle, or, R¹ and R², combined together, formsubstituted or unsubstituted cycloalkyl.

[0018] (7) The modified avermectin aglycon synthase according to (6)above, wherein the N-acetylcysteamine thioester compound is representedby formula (I) in which R¹ is methyl and R² is sec-butyl.

[0019] (8) A DNA which encodes the modified avermectin aglycon synthaseaccording to any one of (1) to (7) above.

[0020] (9) A DNA which comprises a DNA encoding a polypeptide consistingof the amino acid sequence shown in SEQ ID NO: 8.

[0021] (10) A DNA which comprises a DNA consisting of the nucleotidesequence shown in SEQ ID NO: 3.

[0022] (11) A DNA which hybridizes with the DNA according to any one of(8) to (10) above under stringent conditions and encodes a polypeptidehaving an activity for producing 22,23-dihydroavermectin B1a or aderivative thereof when the modified avermectin aglycon synthase iscontacted with the N-acetylcysteamine thioester compound.

[0023] (12) A recombinant DNA which is obtained by ligating the DNAaccording to any one of (8) to (11) above with a vector.

[0024] (13) A transformant which is obtained by introducing therecombinant DNA according to (12) above into a host cell.

[0025] (14) The transformant according to (13) above, wherein the hostcell is a microorganism.

[0026] (15) The transformant according to (14) above, wherein themicroorganism belongs to the genus Streptomyces.

[0027] (16) The transformant according to (15) above, wherein themicroorganism belonging to the genus Streptomyces is Streptomycesavermitilis.

[0028] (17) The transformant according to (16) above, which isStreptomyces avermitilis KS1mut.

[0029] (18) An N-acetylcysteamine thioester compound, which is asubstrate compound for the modified avermectin aglycon synthaseaccording to any one of (1) to (7) above and converted to22,23-dihydroavermectin B1a or a derivative thereof when the compound iscontacted with the modified avermectin aglycon synthase.

[0030] (19) An N-acetylcysteamine thioester compound, which isrepresented by formula (I):

[0031] wherein R¹ and R², which may be the same or different, representhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl or substitutedor unsubstituted heterocycle, or, R¹ and R², combined together, formsubstituted or unsubstituted cycloalkyl.

[0032] (20) The N-acetylcysteamine thioester compound according to (19)above, which is represented by formula (I), wherein R¹ is methyl and R²is sec-butyl.

[0033] (21) A process for producing an N-acetylcysteamine thioestercompound which is characterized by employing as a starting material, acompound represented by formula (II):

[0034] wherein R¹ and R², which may be the same or different, representhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl or substitutedor unsubstituted heterocycle, or, R¹ and R², combined together, formsubstituted or unsubstituted cycloalkyl as a starting material, andincluding a reaction step of adding N-acetylcysteamine.

[0035] (22) The process for producing an N-acetylcysteamine thioestercompound according to (21) above, which is characterized by employing asa starting material, a compound represented by formula (II):

[0036] wherein R¹ and R², which may be the same or different, representhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl or substitutedor unsubstituted heterocycle, or, R¹ and R², combined together, formsubstituted or unsubstituted cycloalkyl, and comprising the steps of:

[0037] (a) ozone-oxidating the compound, and thereafter adding carbonchains by the Wittig reaction;

[0038] (b) deprotecting t-butyldimethylsilyl group of the compoundobtained in step (a) and reintroducing another protecting group usingchlorotriethylsilane;

[0039] (c) reducing α-β unsaturated carbon bond of the resultantcompound in the presence of a palladium-carbon catalyst, hydrolyzing anester with potassium hydroxide, neutralizing the reaction mixture, andadding N-acetylcysteamine in the presence of a condensing agent toobtain a thioester compound; and

[0040] (d) removing the protecting group by adding acetic acid to thethioester compound.

[0041] (23) A process for producing a modified avermectin aglyconsynthase, comprising the steps of:

[0042] culturing the transformant according to any one of (13) to (17)above in a medium untill a modified polypeptide having an activity of aavermectin aglycon synthase is produced and accumulated in the culture;and

[0043] collecting the polypeptide from the culture.

[0044] (24) A process for producing 22,23-dihydroavermectin B1a or aderivative thereof, comprising the steps of:

[0045] contacting a culture of the transformant according to any one of(13) to (17) above or a treated product thereof or the synthaseaccording to any one of (1) to (7) above with the N-acetylcysteaminethioester compound according to claim 18 in a medium; and

[0046] collecting 22,23-dihydroavermectin B1a or a derivative thereofproduced and accumulated in the medium.

[0047] (25) A process for producing 22,23-dihydroavermectin B1a or aderivative thereof, characterized in that an N-acetylcysteaminethioester compound is employed as a substrate compound for the modifiedavermectin aglycon synthase according to any one of (1) to (7) above.

[0048] “The modified avermectin aglycon synthase comprising an aminoacid sequence wherein one or more amino acid residues are deleted,substituted or added in the amino acid sequence of the avermectinaglycon synthase consisting of the amino acid sequence shown in SEQ IDNOs: 4, 5, 6 and 7, and having an activity for producing22,23-dihydroavermectin B1a or a derivative thereof when the modifiedavermectin aglycon synthase is contacted with an N-acetylcysteaminethioester compound” according to (4) above can be obtained byintroducing site-specific mutation into DNA encoding a polypeptidehaving an amino acid sequence shown in SEQ ID NO: 4, 5, 6 or 7 by asite-specific mutation introducing method described in, for example,Molecular Cloning, A laboratory Manual, Second Edition, Cold SpringHarbor Laboratory Press (1989) (hereinafter abbreviated to “MolecularCloning, 2nd Edition”), Current Protocols in Molecular Biology, JohnWiley & Sons (1987-1997) (hereinafter abbreviated to “Current Protocolsin Molecular Biology”), Nucleic Acids Research, 10, 6487 (1982), Proc.Natl. Acad. Sci. USA, 79, 6409 (1982), Gene, 34, 315 (1985), NucleicAcids Research, 13, 4431 (1985), or Proc. Natl. Acad. Sci. USA, 82, 488(1985).

[0049] The number of amino acids to be deleted, substituted or added isnot particularly limited and is preferably one to several decades aminoacids and particularly preferably one to several amino acids.

[0050] In order for the polypeptide of the present invention to have anactivity for producing 22,23-dihydroavermectin B1a or a derivativethereof when the modified avermectin aglycon synthase is contacted withan N-acetylcysteamine thioester compound, the polypeptide is preferablyat least 60%, generally at least 80%, and particularly preferably atleast 95% homologous with the amino acid sequence shown in SEQ ID NO: 1when calculated using BLAST [J. Mol. Biol., 215, 403 (1990)], FASTA[Methods in Enzymology, 183, 63(1990)] and the like.

[0051] “DNA which hybridizes under stringent conditions” according to(11) above refers to DNA that is obtained by employing DNA having anucleotide sequence shown in SEQ ID NO: 3 as a probe through colonyhybridization, plaque hybridization, Southern hybridization or the like.Specifically, it can include DNA which can be identified by performinghybridization in the presence of 0.7 to 1.0 mol/l NaCl at 65° C. using afilter having a colony- or plaque-derived DNA immobilized thereon,followed by washing the filter at 65° C. using a 0.1× to 2×SSC(saline-sodium citrate) solution [1×SSC solution (150 mmol/l NaCl, 15mmol/l sodium citrate) wherein “n x” indicates a n-fold concentratedsolution.

[0052] Hybridization can be carried out in accordance with methodsdescribed in protocols such as Molecular Cloning, 2nd Edition, CurrentProtocols in Molecular Biology, DNA Cloning 1: Core Techniques, and APractical Approach, Second Edition, Oxford University (1995). Specificexamples of hybridizable DNA include DNA which is at least 80%homologous, preferably at least 95% homologous with a nucleotidesequence shown in SEQ ID NO: 3 when calculated using BLAST, FASTA andthe like.

[0053] The present invention will be described in detail below.

[0054] [1] Structural Analysis of Avermectin Aglycon Synthase

[0055] (1) Isolation of Avermectin Aglycon Synthase Gene andDetermination of Nucleotide Sequence

[0056] Methods for isolating avermectin aglycon synthase genes include amethod described in Japanese Published Unexamined Patent Application No.15391/91 and colony hybridization described in Molecular Cloning, 2ndEdition.

[0057] More specifically, chromosomal DNA of Streptomyces avermitilis ispartially digested with a suitable restriction enzyme, for example,Sau3AI. Examples include the following method. A cosmid vector, whichcan replicate in Escherichia coli, is cleaved at a unique restrictionenzyme site, such as the BamHI site. The cleaved cosmid vector is linkedto the digested chromosomal DNA, and Escherichia coli is thentransformed with this recombinant DNA, and a transformant carryingavermectin aglycon synthase genes is selected from the obtainedtransformants by colony hybridization.

[0058] Specific examples of DNA obtained by the method can include DNAhaving the nucleotide sequence shown in SEQ ID NO: 1 or 2. The openreading frames (ORF) contained in these sequences are ORF1 (nucleotidenos. 1 to 11916 of SEQ ID NO: 1), ORF2 (nucleotide nos. 11971 to 30688of SEQ ID NO: 1), ORF3 (nucleotide nos. 1 to 14643 of SEQ ID NO: 2), andORF4 (nucleotide nos. 14824 to 31419 of SEQ ID NO: 2). Examples of theamino acid sequence of the polypeptide encoded by these sequencesinclude sequences respectively shown in SEQ ID NOs: 4, 5, 6 and 7. FIG.1 shows a restriction map of avermectin aglycon synthase gene regions(aveAI and aveAII) in genome DNA of Streptomyces avermitilis togetherwith the deduced transcription unit (arrow).

[0059] (2) Deduction of Module and Domain of Avermectin Aglycon Synthase

[0060] Modules, domains and ORFs, which are relevant to the avermectinaglycon synthase genes, can be determined by comparing similarity withthe sequences of 3 types of polyketide synthase domains of erythromycin[Nature, 348, 176-178 (1990), Science, 252, 675-679 (1991), Eur. J.Biochem., 204, 39-49 (1992)].

[0061] The condensation reaction, which is a basic reaction in thesynthesis of polyketide, requires various catalytic activities includingan acyl carrier protein (ACP), a β-ketoacyl ACP synthase (KS) and anacyltransferase (AT).

[0062] In many cases, β-carbonyl groups generated by the condensationreaction are modified. However, depending on a module, some β-carbonylgroups may not be modified and may be used for the next condensationreaction.

[0063] Catalytic activities associated with the modification of aβ-carbonyl group after the condensation reaction include a β-ketoacylACP reductase (KR), a dehydratase (DH) and an enoyl reductase (ER). Thebiosynthesis of a polyketide chain is terminated by separating from apolyketide synthase by the thioesterase (TE) activity. All or several ofthese modification activities act in each condensation process, therebydetermining the structure of a final product.

[0064] The avermectin aglycon synthase genes (aveAI and aveAII) ofStreptomyces avermitilis are characterized by genes that have severalopen reading frames each of which comprises one or more repeating unitscalled a module, just as the other known polyketide biosynthetic geneshave. The module is defined as a gene fragment which encodes activitiesfor a one-time synthesis, that is, a one-time condensation reaction andother various subsequent modification reactions of the β-carbonyl group.Each module encodes all or several of ACP, KS and AT associated with thecondensation reaction in polyketide synthesis, and KR, DH and ERassociated with the modification reaction of the β-carbonyl group.Furthermore, there is also a module which does not have any domain for amodification reaction. A polypeptide encoded by such a module isreferred to as a synthase unit (SU).

[0065]FIG. 2(b) and (c) show a biosynthetic pathway of6,8a-seco-6,8a-deoxy-5-oxo-avermectin aglycon synthesized withavermectin aglycon synthases of Streptomyces avermitilis.

[0066] PKS-1 is obviously associated with initiation reaction, since theinitiation module (SUs), differing from other modules, hasacyltransferase (AT) activity on the N-terminal side. PKS-3 is alsoobviously associated with the final reaction of polyketide, since module9 (SU9) has a thioesterase (TE) domain.

[0067] Examples of deduced modules of avermectin synthase genes, asynthesis unit encoded by the modules, the domain constituting eachsynthesis unit and a subdomain which is a DNA encoding the domain,include the following sequences.

[0068] The terms used in the present invention are defined as follows.

[0069] Module represents a gene fragment encoding the activities of theone-time condensation reaction and various subsequent modificationreaction of the β-carbonyl group.

[0070] Synthase unit (SU) represents a polypeptide encoded by a module.

[0071] Domain represents polypeptide having each catalytic activityconstituting a synthase unit.

[0072] Subdomain represents a gene fragment encoding a domain.

[0073] These modules are represented as the following nucleotide numbersin SEQ ID NOs: 1 and 2. That is to say, the modules are shown in SEQ IDNO: 1 as,

[0074] Initiation Module: 85 to 1353,

[0075] Module 1: 1441 to 6180,

[0076] Module 2: 6256 to 11658,

[0077] Module 3: 12076 to 15147,

[0078] Module 4: 15217 to 19938,

[0079] Module 5: 20008 to 24690,

[0080] Module 6: 24781 to 30309, and,

[0081] are represented in SEQ ID NO: 2 as,

[0082] Module 7: 100 to 4692,

[0083] Module 8: 4771 to 7818,

[0084] Module 9: 7906 to 14619,

[0085] Module 10: 14935 to 20334,

[0086] Module 11: 20413 to 25734,

[0087] Module 12: 25810 to 31125.

[0088] The amino acid sequences of various synthase units (SU) encodedby these modules are represented as the following amino acids. That isto say, the sequences are represented in SEQ ID NO: 4 as,

[0089] Initiation SU: 29 to 451,

[0090] SU1: 481 to 2060,

[0091] SU2: 2086 to 3886;

[0092] in SEQ ID NO: 5 as,

[0093] SU3: 36 to 1059,

[0094] SU4: 1083 to 2656,

[0095] SU5: 2680 to 4240,

[0096] SU6: 4271 to 6113;

[0097] in SEQ ID NO: 6 as,

[0098] SU7: 34 to 1564,

[0099] SU8: 1591 to 2606,

[0100] SU9: 2636 to 4873; and,

[0101] in SEQ ID NO: 7 as,

[0102] SU10: 38 to 1837,

[0103] SU11: 1864 to 3637,

[0104] SU12: 3663 to 5434.

[0105] DNAs encoding avermectin aglycon synthase domains (subdomains)are represented as the following nucleotide numbers. That is to say, theDNAs are represented in SEQ ID NO: 1 as,

[0106] in Initiation Module,

[0107] ATs: 85 to 1032,

[0108] ACPs: 1096 to 1353;

[0109] in Module 1,

[0110] KS1: 1441 to 2742,

[0111] AT1: 3148 to 4068,

[0112] KR1: 5143 to 5676,

[0113] ACP1: 5935 to 6180;

[0114] in Module 2,

[0115] KS2: 6256 to 7545,

[0116] AT2: 7906 to 8829,

[0117] DH2: 8947 to 9384,

[0118] KR2: 10609 to 11142,

[0119] ACP2: 11413 to 11658;

[0120] in Module 3,

[0121] KS3: 12076 to 13368,

[0122] AT3: 13756 to 14694,

[0123] ACP3: 14902 to 15147;

[0124] in Module 4,

[0125] KS4: 15217 to 16506,

[0126] AT4: 16917 to 17862,

[0127] KR4: 18886 to 19419,

[0128] ACP4: 19693 to 19938;

[0129] in Module 5,

[0130] KS5: 20008 to 21297,

[0131] AT5: 21658 to 22584,

[0132] KR5: 23602 to 24138,

[0133] ACP5: 24445 to 24690;

[0134] in Module 6,

[0135] KS6: 24781 to 26079,

[0136] AT6: 26413 to 27336,

[0137] DH6: 27475 to 27894,

[0138] KR6: 29227 to 29760,

[0139] ACP6: 30064 to 30309; and,

[0140] are also represented in SEQ ID NO: 2 as,

[0141] in Module 7,

[0142] KS7: 100 to 1383,

[0143] AT7: 1648 to 2673,

[0144] KR7: 3634 to 4188,

[0145] ACP7: 4447 to 4692;

[0146] in Module 8,

[0147] KS8: 4771 to 6060,

[0148] AT8: 6322 to 7344,

[0149] ACP8: 7573 to 7818;

[0150] in Module 9,

[0151] KS9: 7906 to 9258,

[0152] AT9: 9676 to 10773,

[0153] DH9: 10885 to 11289,

[0154] KR9: 12547 to 13104,

[0155] ACP9: 13378 to 13659,

[0156] TE9: 13879 to 14619;

[0157] in Module 10,

[0158] KS10: 14935 to 16224,

[0159] AT10: 16543 to 17565,

[0160] DH10: 17689 to 18066,

[0161] KR10: 19285 to 19842,

[0162] ACP10: 20089 to 20334;

[0163] in Module 11,

[0164] KS11: 20413 to 21705,

[0165] AT11: 21991 to 23019,

[0166] DH11: 23149 to 23529,

[0167] KR11: 24685 to 25242,

[0168] ACP11: 25489 to 25734;

[0169] in Module 12,

[0170] KS12: 25810 to 27102,

[0171] AT12: 27367 to 28392,

[0172] DH12: 28516 to 28878,

[0173] KR12: 30076 to 30633,

[0174] ACP12: 30880 to 31125.

[0175] The deduced amino acid sequences of various domains encoded bythese subdomains are represented as:

[0176] in SEQ ID NO: 4,

[0177] ATs: 29 to 344,

[0178] ACPs: 366 to 451,

[0179] KS1: 481 to 914,

[0180] AT1: 1050 to 1356,

[0181] KR1: 1715 to 1892,

[0182] ACP1: 1979 to 2060,

[0183] KS2: 2086 to 2515,

[0184] AT2: 2636 to 2943,

[0185] DH2: 2983 to 3128,

[0186] KR2: 3537 to 3714,

[0187] ACP2: 3805 to 3886;

[0188] in SEQ ID NO: 5,

[0189] KS3: 36 to 466,

[0190] AT3: 596 to 908,

[0191] ACP3: 978 to 1059,

[0192] KS4: 1083 to 1512,

[0193] AT4: 1653 to 1964,

[0194] KR4: 2306 to 2483,

[0195] ACP4: 2575 to 2656,

[0196] KS5: 2680 to 3109,

[0197] AT5: 32030 to 3538,

[0198] KR5: 3878 to 4056,

[0199] ACP5: 4159 to 4240,

[0200] KS6: 4271 to 4703,

[0201] AT6: 4741 to 5048,

[0202] DH6: 5095 to 5234,

[0203] KR6: 5679 to 5856,

[0204] ACP6: 5955 to 6036;

[0205] in SEQ ID NO: 6,

[0206] KS7: 34 to 461,

[0207] AT7: 550 to 891,

[0208] KR7: 1212 to 1396,

[0209] ACP7: 1483 to 1564,

[0210] KS8: 1591 to 2020,

[0211] AT8: 2108 to 2448,

[0212] ACP8: 2525 to 2606,

[0213] KS9: 2636 to 3086,

[0214] AT9: 3226 to 3591,

[0215] DH9: 3629 to 3763,

[0216] KR9: 4183 to 4363,

[0217] ACP9: 4460 to 4553,

[0218] TE9: 4627 to 4873; and,

[0219] in SEQ ID NO: 7,

[0220] KS10: 38 to 467,

[0221] AT10: 574 to 914,

[0222] DH10: 956 to 1081,

[0223] KR10: 1488 to 1673,

[0224] ACP10: 1756 to 1837,

[0225] KS11: 1864 to 2294,

[0226] AT11: 2390 to 2732,

[0227] DH11: 2776 to 2902,

[0228] KR11: 3288 to 3473,

[0229] ACP11: 3556 to 3637,

[0230] KS12: 3663 to 4093,

[0231] AT12: 4182 to 4523,

[0232] DH12: 4565 to 4685,

[0233] KR12: 5085 to 5270,

[0234] ACP12: 5353 to 5434.

[0235] [2] Preparation of Modified Avermectin Aglycon Synthase

[0236] (1) Introduction of Site-Specific Mutation

[0237] DNA which encodes a modified avermectin aglycon synthase having amutation so as to eliminate or significantly lower the activity in atleast one domain is prepared based on the above information. The domainin which the activity is eliminated or significantly lowered may be anyof the above-described domains and are preferably ATs, ACPs, KS1, AT1,KR1, ACP1, KS2, DH2 and KR2.

[0238] Mutations for eliminating or significantly lowering the activityin these domains are not particularly limited. Examples thereof includethe deletion or substitution of an amino acid residue in the activecenter. It is important that an avermectin aglycon synthase protein isproduced by being translated from two large transcription units. Thus,when a termination codon or a frameshift mutation is introduced into thegene existing in the upstream domain of the transcription unit, thetranscription is terminated in mid course and, in some cases, theactivity of the downstream domain is not expressed. In such a case, eventhought there is no mutation existing in the downstream domain of thegene, per se, the entire mutated transcription unit is considered ashaving been deactivated. In order to minimize the influence on theentire transcription unit, the mutation to be introduced is preferablycarried out by preventing the introduction of frameshift or terminationcodon. More preferably, mutation is carried out by substituting aspecific amino acid in an active center with another amino acid.Examples of such mutation include mutation in which serine as an activecenter of AT, serine as an active center of ACP, or cysteine as anactive center of KS [Eur. J. Biochem., 204, 39-49 (1992)] is substitutedwith another amino acid. More specific examples include a mutation inwhich “T” represented as the nucleotide 1969 in the nucleotide sequenceshown in SEQ ID NO: 1 encoding KS1 is substituted with “G.” As a resultof this mutation, a cysteine residue, which is represented as the aminoacid 657 in the amino acid sequence shown in SEQ ID NO: 4, is replacedwith a glycine residue. The cysteine residue, which is represented asthe amino acid 657 in the amino acid sequence shown in SEQ ID NO: 4 isalso conserved in other ketosynthase [Eur. J. Biochem., 204, 39-49(1992)] and is concluded to be essential in expressing the activity inthis domain.

[0239] Methods for introducing mutation are not particularly limited andinclude: a method in which cells having DNA encoding avermectin aglyconsynthase without mutation are subjected to mutation by NTG treatment orUV irradiation; a method in which DNA per se encoding avermectin aglyconsynthase without mutation is processed with a mutagen such ashydroxyurea; and a method in which a site-specific mutation isintroduced based on the nucleotide sequence information of theavermectin aglycon synthase gene. Among these, the method forintroducing site-specific mutation based on the nucleotide sequenceinformation is suitable because a specific mutation can be introducedinto enormous genes such as avermectin aglycon synthase gene withoutcausing any unintended mutation. For example, mutation can be introducedin accordance with methods described in Molecular Cloning, 2nd Edition,Current Protocols in Molecular Biology, Nucleic Acids Research, 10, 6487(1982), Proc. Natl. Acad. Sci. USA, 79, 6409 (1982), Gene, 34, 315(1985), Nucleic Acids Research, 13, 4431 (1985), and Proc. Natl. Acad.Sci. USA, 82, 488 (1985).

[0240] (2) Preparation of Cells Transformed with Recombinant DNA andPreparation of Modified Avermectin Aglycon Synthase

[0241] Methods for obtaining a modified avermectin synthase include amethod using strains having the modified avermectin aglycon synthasedescribed in (1) and a method using a transformant, which is prepared byligating the mutagen-treated DNA or the site-specificmutation-introduced DNA described in (1) and vector DNA to prepare arecombinant DNA, and the recombinant DNA is introduced into a host cell,thereby preparing a transformant. The host cell used in the lattermethod includes bacteria, yeast, filamentous fungus, animal cells, plantcells, and insect cells as long as the introduced modified genes areexpressible in the cell. As an expression vector, it is possible to useany vector that can autonomously replicate in the above host cells orcan be integrated into chromosomes thereof and that contains a promoterat a site which permits transcription of the introduced modified genes(hereinafter referred to as DNA encoding the polypeptide of the presentinvention).

[0242] When a prokaryote (e.g., bacteria) is used as a host cell, apreferred recombinant vector comprising DNA which encodes thepolypeptide of the present invention may be autonomously replicative inprokaryotes and comprises a promoter, a ribosome-binding sequence, theDNA of the present invention and a terminator. The vector may furthercomprise a gene that regulates the promoter.

[0243] Examples of expression vectors include pBTrp2, pBTac1, pBTac2(each of which is commercially available from Boehringer Mannheim),pKK233-2 (manufactured by Pharmacia), pSE280 (manufactured byInvitrogen), pGEMEX-1 (manufactured by Promega), pQE-8, pQE-9, pQE-60,pQE-70 (each of which is manufactured by QIAGEN), pKYP10 (JapanesePublished Unexamined Patent Application No. 110600/83), pKYP200 [Agric.Biol. Chem., 48, 669 (1984)], pLSA1 [Agric. Biol. Chem., 53, 277(1989)], pGEL1 [Proc. Natl. Acad. Sci. USA, 82, 4306 (1985)],pBluescript II SK(−) (manufactured by Stratagene), pTrS30 [prepared fromEscherichia coli JM109/pTrS30 (FERM BP-5407)], pTrS32 [prepared fromEscherichia coli JM109/pTrS32 (FERM BP-5408)], pGHA2 [prepared fromEscherichia coli IGHA2 (FERM BP-400), Japanese Published UnexaminedPatent Application No. 221091/85], pGKA2 [prepared from Escherichia coliIGKA2 (FERM BP-6798), Japanese Published Unexamined Patent ApplicationNo. 221091/85], pTerm2 (U.S. Pat. No. 4,686,191, U.S. Pat. No.4,939,094, U.S. Pat. No. 5,160,735), pSupex, pUB110, pTP5, pC194, pEG400[J. Bacteriol., 172, 2392 (1990)], pGEX (manufactured by Pharmacia),pUC19 [Gene, 33, 103 (1985)], pUC118 (manufactured by Pharmacia), pETsystem (manufactured by Novagen), pIJ702, and pIJ922, etc.

[0244] Examples of chromosomal integration vectors include a vectorderived from actinophage R4 [J. Bacteriol., 173, 4237 (1991)].

[0245] Examples of homologous recombination vectors include pKC7(Japanese Published Unexamined Patent Application No. 189774/94).

[0246] Any promoter capable of functioning in host cells may be used,including promoters derived from Escherichia coli or a phage such as trppromoter (Ptrp), lac promoter (Plac), P_(L) promoter, P_(R) promoter andT7 promoter. An artificially designed, modified promoter may also beused, including a promoter obtained by binding two Ptrp promoters intandem (Ptrp×2), tac promoter, lac T7 promoter and let I promoter.

[0247] It is preferable to use a plasmid having an appropriate distance(e.g., 6-18 nucleotides) between Shine-Dalgarno sequence (i.e.,ribosome-binding sequence) and an initiation codon. In the recombinantvector of the present invention, a terminator is not necessarilyrequired for the expression of the DNA of the present invention, but itis desirably located immediately downstream of a structural gene.

[0248] Host cells include a microorganism belonging to Escherichia,Serratia, Bacillus, Brevibacterium, Corynebacterium, Microbacterium,Pseudomonas, Streptomyces and the like. Specific examples includeEscherichia coli XL1-Blue, Escherichia coli XL2-Blue, Escherichia coliDH1, Escherichia coli MC1000, Escherichia coli KY3276, Escherichia coliW1485, Escherichia coli JM109, Escherichia coli HB101, Escherichia coliNo.49, Escherichia coli W3110, Escherichia coli NY49, Escherichia coliG1698, Escherichia coli TB1, Serratia ficaria, Serratia fonticola,Serratia liquefaciens, Serratia marcescens, Bacillus subtilis, Bacillusamyloliquefacines, Brevibacterium ammoniagenes, Brevibacteriumimmariophilum ATCC14068, Brevibacterium saccharolyticum ATCC14066,Brevibacterium flavum ATCC14067, Brevibacterium lactofermentumATCC13869, Corynebacterium glutamicum ATCC13032, Corynebacteriumglutamicum ATCC 13869, Corynebacterium acetoacidophilum ATCC 13870,Microbacterium ammoniaphilum ATCC15354, Pseudomonas putida, Pseudomonassp. D-0110, Streptomyces lividans TK23, Streptomyces lividans ATCC69411,Streptomyces coelicolor ATCC13405, Streptomyces griseus ATCC23915,Streptomyces avermitilis ATCC31267, Streptomyces avermitilis FERMBP-2773, and Streptomyces avermitilis FERM BP-2775, etc.

[0249] The recombinant vector may be introduced by any of the method forintroducing DNA into the above host cells: for example, the method usingcalcium ion [Proc. Natl. Acad. Sci. USA, 69, 2110 (1972)], theprotoplast method (Japanese Published Unexamined Patent Application No.248394/88) and the method described in Gene, 17, 107 (1982) andMolecular & General Genetics, 168, 111 (1979).

[0250] When yeast is used as a host cell, examples of usable expressionvector include YEP13 (ATCC37115), YEp24 (ATCC37051), YCp50 (ATCC37419),pHS19 and pHS15, etc.

[0251] Any promoter capable of functioning in yeast cells may be used,including glycolytic gene promoters such as hexose kinase, PHO5promoter, PGK promoter, GAP promoter, ADH promoter, gal 1 promoter, gal10 promoter, heat shock polypeptide promoter, MF α1 promoter and CUP 1promoter.

[0252] Host cells include microorganisms belonging to Saccharomyces,Schizosaccharomyces, Kluyveromyces, Trichosporon, Schwanniomyces, Pichiaand the Candida. Specific examples include Saccharomyces cerevisiae,Schizosaccharomyces pombe, Kluyveromyces lactis, Trichosporon pullulans,Schwanniomyces alluvius, or Candida utilis, etc.

[0253] The recombinant vector may be introduced by any of the method forintroducing DNA into yeast: for example, electroporation [MethodsEnzymol., 194, 182 (1990)], the spheroplast method [Proc. Natl. Acad.Sci. USA, 75, 1929 (1978)], the lithium acetate method [J. Bacteriology,153, 163 (1983)] and the method described in Proc. Natl. Acad. Sci. USA,75, 1929 (1978).

[0254] When an animal cell is used as a host cell, examples of usableexpression vectors include pcDNAI, pcDM8 (manufactured by Funakoshi),pAGE107 [Japanese Published Unexamined Patent Application No. 22979/91,Cytotechnology, 3, 133 (1990)], pAS3-3 (Japanese Published UnexaminedPatent Application No. 227075/90), pCDM8 [Nature, 329, 840 (1987)],pcDNAI/Amp (manufactured by Invitrogen), pREP4 (manufactured byInvitrogen), pAGE103 [J. Biochem., 101, 1307 (1987)], and pAGE210, etc.

[0255] Any promoter capable of functioning in animal cells may be used,including a promoter for immediate early (1E) gene of Cytomegalovirus(CMV), SV40 early promoter, retroviral promoter, metallothioneinpromoter, heat shock promoter, and SRapromoter. An enhancer for IE geneof Human CMV may also be used together with such a promoter.

[0256] Host cells include human Namalwa cells, monkey COS cells, chinesehamster CHO cells, or HBT5637 (Japanese Published Unexamined PatentApplication No. 299/88).

[0257] The recombinant vector may be introduced into animal cells by anyof the method for introducing DNA into animal cells: for example,electroporation [Cytotechnology, 3, 133 (1990)], calcium phosphatemethod (Japanese Published Unexamined Patent Application No. 227075/90),lipofection method [Proc. Natl. Acad. Sci. USA, 84, 7413 (1987)] and themethod described in Virology, 52, 456 (1973), etc.

[0258] When an insect cell is used as a host cell, a polypeptide may beexpressed by a method described in Current Protocols in MolecularBiology; Baculovirus Expression Vectors, A Laboratory Manual, W. H.Freeman and Company, New York (1992); or Bio/Technology, 6, 47 (1988).

[0259] More specifically, a recombinant gene-transfer vector and abaculovirus may be co-introduced into insect cells to obtain arecombinant virus in the supernatant from the culture of insect cells.Thereafter, insect cells may be further infected with the resultingrecombinant virus to express the polypeptide.

[0260] A gene-transfer vector to be used in the above procedure includespVL1392, pVL1393 and pBlueBacIII (manufactured by Invitrogen,respectively). As a baculovirus, for example, Autographa californicanuclear polyhedrosis virus, which infects Noctuidae insects, may beused.

[0261] Insect cells include Spodoptera frugiperda ovarian cells, Sf9 andSf21, [Baculovirus Expression Vectors, A Laboratory Manual, W. H.Freeman and Company, New York (1992)], and Trichoplusia ni ovariancells, High 5, (manufactured by Invitrogen), etc.

[0262] Co-introduction of the recombinant gene-transfer vector and thebaculovirus into insect cells for recombinant virus production may beaccomplished by the calcium phosphate method (Japanese PublishedUnexamined Patent Application No. 227075/90) or the lipofection method[Proc. Natl. Acad. Sci. USA, 84, 7413 (1987)].

[0263] When a plant cell is used as a host cell, examples of anexpression vector include Ti plasmid and tobacco mosaic virus vector,etc.

[0264] Any promoter capable of functioning in plant cells may be used,including cauliflower mosaic virus (CaMV) 35S promoter and rice actin 1promoter.

[0265] Host cells include plant cells such as tobacco, potato, tomato,carrot, soy bean, Brassica, alfalfa, rice, wheat and barley.

[0266] The recombinant vector may be introduced by any method forintroducing DNA into plant cells: for example, Agrobacterium method(Japanese Published Unexamined Patent Application No. 140885/84,Japanese Published Unexamined Patent Application No. 70080/85,WO94/00977), electroporation method (Japanese Published UnexaminedPatent Application No. 251887/85), and particle gun method (JapanesePatent No. 2606856, Japanese Patent No. 2517813).

[0267] The polypeptide of the present invention may be obtained byculturing a transformant of the present invention prepared as statedabove in a medium until the polypeptide of the present invention isproduced and accumulated in the culture, and collecting the polypeptidefrom the culture.

[0268] The transformant of the present invention may be cultured in amedium according to a conventional method used for culturing host cells.

[0269] When the transformant of the present invention is derived from aprokaryotic host such as Escherichia coli or a eukaryotic host such asyeast, the medium for culturing the transformant may be a natural orsynthetic medium insofar as the medium contains a carbon source, anitrogen source, inorganic salts etc., which can be assimilated by thetransformant, and enables efficient culturing of the transformant.

[0270] Any carbon source assimilated by the transformant can be used.Examples include carbohydrates such as glucose, fructose, sucrose,molasses containing the same, starch and starch hydrolysates; organicacids such as acetic acid and propionic acid alcohols such as ethanoland propanol.

[0271] Examples of usable nitrogen source include ammonia, ammoniumsalts of inorganic or organic acids, such as ammonium chloride, ammoniumsulfate, ammonium acetate, and ammonium phosphate; othernitrogen-containing compounds; and peptones, meat extracts, yeastextracts, corn steep liquor, casein hydrolysates, soy bean meal, soybean meal hydrolysates, various fermented microorganism cells andhydrolysates thereof.

[0272] Inorganic salts usable herein include potassium dihydrogenphosphate, dipotassium hydrogen phosphate, magnesium phosphate,magnesium sulfate, sodium chloride, ferrous sulfate, manganese sulfate,copper sulfate, calcium carbonate, and the like.

[0273] Culturing is carried out under aerobic conditions as used forshaking culture or submerged aeration stirring culture. Culturetemperature is preferably 15 to 40° C., and culture duration is usuallyfor 16 hours to 7 days. During the culture, pH is preferably maintainedat 3.0 to 9.0. pH is adjusted by using an inorganic or organic acid, analkaline solution, urea, calcium carbonate, ammonia and the like.

[0274] If necessary, antibiotics such as ampicillin and tetracycline maybe added to a medium during the culture.

[0275] Where a microorganism is transformed with a recombinant vectorthat contains inducible promoter, the transformant may be cultured in amedium supplemented with an inducer, if necessary. For example, in thecase of a microorganism transformed with a recombinant vector comprisinglac promotor, isopropyl-β-D-thiogalactopyranoside or the like may be addto the medium, and in the case of a microorganism transformed with arecombinant vector comprising trp promoter, indole acrylic acid or thelike may be added.

[0276] A medium for culturing a transformant derived from an animal hostcell may be a generally used medium such as RPMI 1640 medium [TheJournal of the American Medical Association, 199, 519 (1967)], Eagle'sMEM medium [Science, 122, 501 (1952)], Dulbecco's modified MEM medium[Virology, 8, 396 (1959)], 199 medium [Proceeding of the Society for theBiological Medicine, 73, 1 (1950)] or any one of these media furthersupplemented with fetal calf serum.

[0277] Culturing is usually carried out at pH 6 to 8, at a temperatureof 30 to 40° C. for a period of 1 to 7 days in the presence of 5% CO₂.

[0278] If necessary, antibiotics such as kanamycin and penicillin may beadded to the medium during the culture.

[0279] The medium for culturing a transformant derived from an insecthost cell may be a generally used medium such as TNM-FH medium(manufactured by Pharmingen), Sf-900 II SFM medium (manufactured by LifeTechnologies), ExCell 400 and ExCell 405 [both manufactured by JRHBiosciences], Grace's Insect Medium [Nature, 195, 788 (1962)] or thelike.

[0280] Culturing is carried out at pH 6 to 7, at a temperature of 25 to30° C. for a period of 1 to 5 days.

[0281] If necessary, antibiotics such as gentamycin may be added to themedium during the culture.

[0282] The transformant derived from a plant host cell may be culturedas a cell or may be allowed to differentiate into plant cells or organs.The medium for culturing such a transformant may be a generally usedmedium such as Murashige and Skoog (MS) medium, White medium, or any oneof these media further supplemented with a plant hormone such as auxinor cytokinin.

[0283] Culturing is usually carried out at pH 5 to 9, at a temperatureof 20 to 40° C. for a period of 3 to 60 days.

[0284] If necessary, antibiotics such as kanamycin and hygromycin may beadded to a medium during the culture.

[0285] As stated above, the polypeptide of the present invention may beobtained by culturing a microorganism-, animal cell-, or plantcell-derived transformant carrying a recombinant vector comprising a DNAthat encodes the polypeptide in a general manner to produce andaccumulate the polypeptide, and then recovering the polypeptide from theculture.

[0286] A gene of interest may be either expressed directly, or as asecretory protein or fusion polypeptide according to the method asdescribed in Molecular Cloning, 2nd Edition.

[0287] Expression in yeast, animal, insect or plant cells can provide apolypeptide with sugar or sugar chain added thereto.

[0288] The protein of the present invention may be produced byintracellular production by host cells, extracellular secretion by hostcells or production on outer membranes by host cells. Such productionmethod can be selected depending on the kind of the host cells used oron alteration of the structure of the portein.

[0289] If the polypeptide of the present invention is produced in hostcells or on the outer membranes of host cells, the polypeptide can beefficiently secreted extracellularly from the host cells by using themethod of Paulson et al. [J. Biol. Chem., 264, 17619 (1989)], the methodof Lowe et al. [Proc. Natl. Acad. Sci. USA, 86, 8227 (1989), GenesDevelop., 4, 1288 (1990)] or methods as described in Japanese PublishedUnexamined Patent Application Nos. 336963/93 and 823021/94.

[0290] More specifically, the polypeptide of the present invention canbe efficiently secreted from host cells by expressing it with a signalpeptide, then using genetic recombination techniques, adding the signalpeptide upstream of a polypeptide containing the active site of thepolypeptide of the present invention.

[0291] Polypeptide production can be enhanced by utilizing a geneamplification system that uses a dihydrofolate reductase gene or thelike according to the method described in Japanese Published UnexaminedPatent Application No. 227075/90.

[0292] Further, animal or plant cells carrying a transgene may bere-differentiated to create an animal individual carrying a transgene(transgenic non-human animal) or a plant individual carrying a transgene(transgenic plant), which may be used for producing the polypeptide ofthe present invention.

[0293] When the transformant is an animal or plant individual, thepolypeptide may be obtained by feeding or cultivating the individual ina general manner to produce and accumulate the polypeptide, and thenrecovering the polypeptide from the animal or plant individual.

[0294] In order to produce the polypeptide of the present inventionusing an animal individual, for example, an animal carrying a transgenemay be allowed to produce therein the polypeptide of the presentinvention in a known manner as described in American Journal of ClinicalNutrition, 63, 639S (1996); American Journal of Clinical Nutrition, 63,627S (1996); and Bio/Technology, 9, 830 (1991).

[0295] In the case of an animal individual, for example, the polypeptideof the present invention may be obtained by feeding a transgenicnon-human animal carrying a DNA insert that encodes the polypeptide ofthe present invention to produce and accumulate therein the polypeptide,and then collecting the polypeptide from the animal. The polypeptide maybe produced and accumulated in the animal's milk (Japanese PublishedUnexamined Patent Application No. 309192/88), egg and the like. Anypromoter capable of functioning in an animal may be used, for example,mammary gland cell-specific promoters such as α-casein promoter,β-casein promoter, β-lactoglobulin promoter and whey acidic proteinpromoter being preferred.

[0296] In order to produce the polypeptide of the present inventionusing a plant individual, for example, a transgenic plant carrying a DNAinsert encoding the polypeptide of the present invention may becultivated to produce and accumulate therein the polypeptide in a knownmanner as described in Tissue Culture (Soshiki Baiyo), 20 (1994); TissueCulture, 21 (1995); and Trends in Biotechnology, 15, 45 (1997), and thenthe polypeptide may be recovering from the plant.

[0297] For isolation and purification of the polypeptide produced fromthe transformant of the present invention, conventional methods for theisolation and purification of enzymes can be used.

[0298] For example, if the polypeptide of the present invention isexpressed in a soluble form in cells, after completion of culturing, thecells are collected by centrifugation, suspended in an aqueous bufferand then disrupted with ultrasonic disrupter, French Press,Manton-Gaulin homogenizer, Dynomill or the like, thereby obtaining acell-free extract. A purified preparation can be obtained bycentrifuging the cell-free extract. The obtained supernatant is thensubjected to conventional isolation and purification methods forenzymes, i.e., solvent extraction, salting-out or desalting with sulfateammonium etc., precipitation with organic solvent, anion-exchangechromatography on resin such as diethylaminoethyl (DEAE)-Sepharose orDIAION HPA-75 (manufactured by Mitsubishi Chemical Industries Ltd.),cation-exchange chromatography on resin such as S-Sepharose FF(manufactured by Pharmacia), hydrophobic chromatography on resin such asbutyl Sepharose or phenyl Sepharose, gel filtration using molecularsieve, affinity chromatography, chromatofocusing, or electrophoresissuch as isoelectric focusing, or combinations thereof.

[0299] If the polypeptide is expressed as inclusion body in cells, thecells are similarly collected, disrupted and centrifuged to give aninsoluble matter of the polypeptide as a precipitated fraction. Theresulting insoluble polypeptide is then solubilized with aprotein-denaturing agent. The solubilized solution is then diluted ordialyzed to reduce the agent to a lower concentration, thereby allowingthe polypeptide to be renatured to its normal conformation. The purifiedpreparation of the polypeptide can be then obtained by use of the sameisolation and purification methods as described above.

[0300] If the polypeptide of the present invention or a derivativethereof having a sugar chain added thereto is extracellularly secreted,the polypeptide or its derivatives may be recovered in the culturesupernatant. Namely, the culture is subjected to the same process, suchas centrifugation, as described above to give a culture supernatant.From the culture supernatant, a purified preparation can be obtained inthe same manner for isolation and purification as described above.

[0301] The polypeptide thus obtained may be, for example, a polypeptidehaving the amino acid sequence shown in SEQ ID NO: 8.

[0302] The polypeptide of the present invention may be produced bychemical synthesis methods including Fmoc method (fluorenylmethyloxycarbonyl method), t-Boc method (t-butyloxycarbonyl method), andso on. Also, it may be chemically synthesized using a peptidesynthesizer available from Advanced ChemTech, Perkin Elmer, Pharmacia,Protein Technology Instrument, Synthecell-Vega, PerSeptive or ShimadzuCorporation, etc.

[0303] In contrast, a method for inserting DNA having mutation which hasbeen introduced in vitro into the chromosomal DNA of the host cell canbe carried out by any method utilizing the homologous recombination ofDNA. Examples of such methods include a method described in JapanesePublished Unexamined Patent Application No. 189774/94.

[0304] Cells having a modified avermectin aglycon synthase gene havingmutation introduced as described above are not particularly limitedinsofar as cells can carry the gene and may be any prokaryotic cellssuch as Escherichia coli, Bacillus subtilis, and Actinomyces. Examplesthereof include microorganisms belonging to Streptomyces avermitilis.

[0305] [3] Preparation of Substrate Compound for Producing22,23-dihydroavermectin B1a or Derivative Thereof.

[0306] In the present invention, the substrate compound for producing22,23-dihydroavermectin B1a or a derivative thereof may be any substanceinsofar as the substance can be used as a substrate for the modifiedavermectin aglycon synthase as described above. More specifically, inthe process for synthesizing avermectin aglycon, the substance can be asubstrate for the domain responsible for the later reaction step in themodified domain and an N-acetylcysteamine compound is preferably used.For example, when the KS domain of SU1 shown in FIG. 2 is modified, theN-acetylcysteamine compound preferably has a structure as represented byformula (I):

[0307] wherein R¹ and R², which may be the same or different, representhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl, or substitutedor unsubstituted heterocycle, or, R¹ and R² together form, substitutedor unsubstituted cycloalkyl.

[0308] In defining each group in formula (I), examples of alkyl includestraight chain or branched C₁₋₂₀ methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,heptyl, decyl, dodecyl, pentadecyl, and eicosyl, etc.

[0309] Examples of alkenyl include straight chain or branched C₂₋₂₀vinyl, allyl, 1-propenyl, methacryl, chrotyl, 1-butenyl, 3-butenyl,2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl, heptenyl, decenyl,dodecenyl, pentadecenyl, and eicosenyl, etc.

[0310] Examples of aryl include C₆₋₁₄ phenyl, naphthyl, and anthryl,etc.

[0311] Examples of heterocycle include aromatic heterocycle such aspyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthylizinyl, cinnolinyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl, furyl,thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl,benzothiazolyl, benzoxazolyl, and purinyl; and alicyclic heterocyclesuch as pyrrolidinyl, piperidino, piperazinyl, morpholino,thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl,tetrahydropiranyl, and dihydrobenzofuranyl, etc.

[0312] Examples of cycloalkyl include C₃₋₈ cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, etc.

[0313] Substituted alkyl, substituted alkenyl, and substitutedcycloalkyl may be mono-, di-, tri-substituted and each substituent isthe same or different. Example of substituents include hydroxy andsubstituted or unsubstituted alkoxy. The alkyl portion of alkoxy has thesame meaning as the above alkyl and substituted alkoxy may be mono-,di-, tri-substituted by, for example, hydroxy.

[0314] Substituted aryl and substituted heterocycle may be mono-, di-,tri-substituted and each substituent is the same or different. Exampleof substituents include hydroxy, substituted or unsubstituted loweralkyl, and substituted or unsubstituted lower alkoxy, etc. The loweralkyl and lower alkoxy have the same meaning as the above andsubstituted lower alkyl and substituted lower alkoxy may be mono-, di-,tri-substituted by, for example, hydroxy.

[0315] Specific examples of such compounds include a compound (Compound4 shown in the table below) represented by the above formula, wherein R¹is methyl and R² is sec-butyl. The compound employs, for example,Compound A shown in the table below as a starting material and can bechemically synthesized in the following manner through Compounds 1 to 3similarly shown in the table.

[0316] At the outset, Compound 1 is prepared using Compound A as astarting material and performing ozone oxidation, followed by the Wittigreaction to add carbon chains. After t-butyldimethylsilyl of Compound 1is deprotected, a protective group is reintroduced usingchloroethyl-tri-silane to obtain Compound 2. Subsequently, α-βunsaturated carbon bond in compound 2 is reduced in the presence of apalladium-carbon catalyst, ester is hydrolyzed with potassium hydroxideand neutralized, followed by the addition of N-acetylcysteamine in thepresence of a condensing agent. Thus, a thioester compound, Compound 3,is obtained. Finally, acetic acid is added to Compound 3 to remove theprotective group. Thus, Compound 4 is prepared.

[0317] Other compounds represented by formula (I) can also be producedin the same manner.

[0318] The intermediates and the compounds of interest in the aboveproduction method are subjected to separation purification methods,which are commonly used in organic synthetic chemistry, for example,filtration, extraction, washing, drying, concentration,recrystallization, or various chromatographies and, thus, they can beisolated and purified. The intermediate can be applied to the subsequentreaction without purification. TABLE 1 Compounds A

1

2

3

4

[0319] [4] Production of 22,23-dihydroavermectin B1a or DerivativeThereof.

[0320] Any of the culture, cells or treated cells of the cells obtainedby transforming the host cell in [2]-2 can be used in the reaction withthe substrate compounds so far as the modified avermectin aglyconexpressed in the transformed cell are functioned.

[0321] Treated cells include dried cells, freeze-dried products,surfactant- or organic solvent-processed products, enzyme-processedproducts, ultrasonicated products, mechanically ground products, proteinfractions of cells, and immobilized cells of treated cells.

[0322] Any method of making the substrate compound acting upon thetransformed host cell can be used so far as the synthesis of avermectinaglycon is disturbed. Specific examples thereof include a method inwhich the culture of cells or treated products thereof are reacted withthe substrate in a suitable medium and a method in which the cells arecultured by adding the substrate in initially or mid course of theculturing.

[0323] Media used in the reaction include water, buffers such asphosphate, carbonate, acetate, borate, citrate and Tris, aqueoussolutions containing organic solvents, for example, alcohols such asmethanol and ethanol, esters such as ethyl acetate, ketones such asacetone, and amides such as acetamide. If necessary, surfactants such asTriton X-100 (manufactured by Nacalai Tesque, Inc.) or Nonion HS204(manufactured by NOF Corp.) or organic solvents such as toluene andxylene may be added in an amount of about 0.1 to 20 g/l.

[0324] Reaction is carried out in the above aqueous solution at pH 5 to10, preferably pH 6 to 8, at 20 to 50° C. for 1 to 96 hours.

[0325] When the host cell is cultured in a medium, culture can becarried out in the same manner as for obtaining the polypeptide.

[0326] 22,23-dihydroavermectin B1a or a derivative thereof can beisolated from the reaction product or the culture obtained by any of theabove methods in accordance with conventional isolation methods. Forexample, the cultured cell is treated with acetone or methanol toextract 22,23-dihydroavermectin B1a or a derivative thereof and, afterthe removal of the residue, concentrated. The concentrate is processedwith methylene chloride, the methylene chloride layer is fractionatedand further concentrated under reduced pressure. Thus, the subjectcompound can be obtained.

BRIEF DESCRIPTION OF DRAWINGS

[0327]FIG. 1 is a diagram showing a restriction map of BamHI, BglII,ClaI, EcoRI, KpnI, Mlul, PstI, StuI, and XhoI sites of avermectinaglycon synthase genes aveAI and aveAII of Streptomyces avermitilis. Thearrows indicate the deduced transcription direction of each gene.

[0328]FIG. 2(a) shows the location of avermectin aglycon synthase geneson the chromosome and the domain sequence of synthase units, FIGS. 2(b)and 2(c) show the deduced steps of avermectin aglycon synthesis, andFIG. 2(d) shows the structure of 6,8-sec-6,8a-deoxy-5-oxoavermectinaglycon and the location of integrated lower fatty acids in its skeletonwhich had been synthesized by a polyketide synthase, which is a geneproduct of avermectin aglycon synthase genes aveAI and aveAII.

[0329] (Description of Reference Characters)

[0330] ACP: acyl carrier protein

[0331] KS: β-ketoacyl ACP synthase

[0332] AT: acyltransferase

[0333] KR: β-ketoacyl ACP reductase

[0334] DH: dehydratase

[0335] ER: enoyl reductase

[0336] TE: thioesterase

[0337]FIG. 3 is a diagram showing a procces for constructing a plasmidto be used in the transformation of Streptomyces avermitilis wherein (I)shows plasmid pKS1 prepared by cloning KS1 containing DNA encoding anamino acid residue in an active center, (II) shows plasmid pKSmutprepared by cloning DNA encoding KS1 prepared by substituting an aminoacid residue in an active center, (III) shows plasmid pKSmutRL preparedby applying addition and substitution of a DNA fragment shown in (IV) topKSmut, and (IV) is the restriction map of DNA encoding KS1 used in theconstruction of pKSmutRL.

[0338] In the drawing, “

” indicates the location of the nucleotides which have been substituted,and HindIII, PstI, BamHI, KpnI, and EcoRI indicate the DNA cleavagesites of each restriction enzyme. Numerical values in (I), (II), and(III) indicate, when a desired nucleotide of each plasmid is determinedas No. 1, the distance (bp) from the nucleotide and numerical valueswith in the circle indicate the total plasmid length (bp). Numericalvalues in (IV) are in accordance with the nucleotides shown in SEQ IDNO: 1. Abbreviations in the drawings are as follows.

[0339] (Description of Reference Characters)

[0340] bla: β-lactamase (arrow indicates the direction of transcription)

[0341] ori: replication origin (origin)

[0342] Plac: β-lactamase promoter (arrow indicates the direction of thepromoter)

[0343] IG: M13 phage intergenic region (M13 Intergenic region)

BEST MODES FOR CARRYING OUT THE INVENTION

[0344] The present invention will be described in more detail withreference to examples; however, these examples are not intended to limitthe scope of the present invention.

EXAMPLE 1 Determination of Nucleotide Sequence and Structure ofAvermectin Aglycon Synthase Gene

[0345] A nucleotide sequence of DNA encoding avermectin aglycon synthasederived from Streptomyces avermitilis K2033 (U.S. Pat. No. 5,206,155,FERM BP-2773) was determined as follows.

[0346] A continuous or overlapping DNA fragment within the avermectinaglycon synthase gene was subcloned from a cosmid containing fragmentsof the avermectin aglycon synthase genes (aveAI and aveAII) co-isolatedwith a gene encoding avermectin B5-O-transmethylase [aveD; Gene, 206,175-180 (1998)]. Nucleotide sequences of the inserted DNA fragments inthese subclones were then determined.

[0347] More specifically, the entire nucleotide sequences of aveAI andaveAII were determined by subcloning BamHI-digested fragments of 3.4kbp, 2.0 kbp, 0.5 kbp, 6.8 kbp, 7.0 kbp, 7.8 kbp, 3.7 kbp, 4.8 kbp, 1.3kbp, 2.4 kbp, 0.7 kbp, 1.0 kbp, 5.4 kbp, 2.5 kbp, 1.9 kbp, 0.1 kbp, 7.0kbp, 3.1 kbp, 4.7 kbp and 1.3 kbp found in the BamHI-restriction map ofaveAI and aveAII shown in FIG. 1; digesting the inserted DNA fragmentsin these subclones with exonuclease III and S1 nuclease to prepare aseries of deletion fragments; and then performing a cycle-sequencingreaction using fluorescently-labeled primers to determine a nucleotidesequence of each deleted fragment. aveAI and aveAII had the nucleotidesequences shown in SEQ ID NO: 1 and SEQ ID NO: 2, respectively.

EXAMPLE 2 Preparation of Strain Applied for the Direct Production of22,23-dihydroavermectin B1a

[0348] The plasmid shown in FIG. 3 was produced in accordance with thefollowing method and used in the transformation of Streptomycesavermitilis.

[0349] (1) Subcloning of a DNA Fragment Containing KS1

[0350] The cosmid DNA containing KS1, from among cosmid DNAs containingavermectin aglycon synthase genes, was digested with the restrictionenzyme BamHI (manufactured by Takara Shuzo Co., Ltd.) followed byagarose gel electrophoresis (described in Molecular Cloning, 2ndEdition), and 2.0 kb DNA fragment (see FIG. 1, 1701 to 3716 shown in SEQID NO: 1) containing a cysteine residue (amino acid 657 shown in SEQ IDNO: 4), which is an active center of KS1, was separated and purified inaccordance with the method described in Molecular Cloning, 2nd Edition.Plasmid pUC118 (manufactured by Takara Shuzo Co., Ltd.) was digestedwith BamHI and dephosphorylated with alkaline phosphatase from calfintestine (manufactured by Takara Shuzo Co., Ltd.). About 0.1 μg each of2.0 kb DNA fragment containing KS1 and a BamHI digested pUC118 wereligated 16° C. for 16 hours using Ligation High (manufactured by ToyoboCo., Ltd.). 10 μl of this DNA ligation reactant was brought into contactwith a competent cell of Escherichia coli DH5a (manufactured by NipponGene Co., Ltd.) and transformed in accordance with the method describedin Molecular Cloning, 2nd Edition. In selecting the transformant, an LBagar medium containing 50 μg/ml ampicillin (manufactured by Wako PureChemical Industries, Ltd.) was used. 50 μl of aqueous solution of 0.1mol/l isopropyl-β-D-thiogalactopyranoside (IPTG, manufactured by WakoPure Chemical Industries, Ltd.) and 50 μl of 2% solution of5-bromo-4-chloro-3-indolyl-β-D-galactoside (X-gal, manufactured byNacalai Tesque, Inc.) in dimethylformamide (manufactured by NacalaiTesque, Inc.) were previously spread on the 20 ml of LB agar medium. Thecolony of the transformant carrying the recombinant plasmid has lost itsβ-galactosidase activity, and thus, cannot decompose5-bromo-4-chloro-3-indolyl-β-D-galactoside while developing white color.This white colony was collected with the aid of ase, inoculated on 10 mlof LB medium, and subjected to shaking culture at 37° C. for 16 hours.The plasmid was then extracted from the cells and purified in accordancewith the alkaline method described in Molecular Cloning, 2nd Edition. Apart of the resulting recombinant plasmid was digested with arestriction enzyme PstI and it was confirmed that plasmid pKS1, intowhich a DNA fragment containing KS1 genes was inserted in the samedirection with lacZ encoded by pUC118, was obtained.

[0351] (2) Introduction of Nucleotide Substitution into the ActiveCenter of KS1

[0352] Nucleotide was substituted using Takara LA PCR in vitroMutagenesis Kit (manufactured by Takara Shuzo Co., Ltd.). Nucleotide washereinafter substituted in accordance with the protocol attached to thekit. The recombinant plasmid containing KS1 genes prepared in (1) abovewas used as template DNA for the 1st PCR. As a primer for the 1stPCR-(a), 5′-ACCGTGGACACGGGGGGCTCGGCATCGCTCGT-3′ shown in SEQ ID NO: 9(corresponding to 1954 to 1985 shown in SEQ ID NO: 1, “T” at the 1969position was substituted with “G”) and M13M4 primer (attached to thekit) were used as a primer for introducing mutation. M13RV primer andMUT4 primer (attached to the kit) were used as primers for the 1stPCR-(b). In the 1st PCR, incubation at 98° C. for 5 minutes, and then 30cycles of reaction constituted by 30 seconds at 94° C., 2 minutes at 55°C. and 3 minutes at 72° C. as one cycle were carried out. TaKaRa PCRThermal Cycler 480 (manufactured by Takara Shuzo Co., Ltd.) was used inPCR. Each reaction solution was subjected to agarose gel electrophoresisand about 1.8 kb amplified fragment in the 1st PCR-(a) and about 2.0 kbamplified fragment in the 1st PCR-(b) were respectively separated andpurified for use in the subsequent step. Heteroduplex DNA betweenamplified fragments obtained in the 1st PCR was formed by incubating at98° C. for 15 minutes, lowering the temperature to 37° C. over thecourse of 1 hour, and then incubating at 37° C. for 15 minutes. After LATaq polymerase was added to the reaction solution, the mixture wasincubated at 72° C. for 3 minutes to convert the terminus of theheteroduplex DNA into a blunt-ended terminus. In the subsequent 2nd PCR,30 cycles of reaction constituted by 20 seconds at 94° C., 30 seconds at60° C. and 3 minutes at 72° C. as one cycle were carried out. A part ofthe 2nd PCR product was subjected to agarose gel electrophoresis and theamplification of about 2.0 kb fragment was confirmed. The remainingsolution of the 2nd PCR was thoroughly mixed with aphenol:chloroform=1:1 solution saturated with water and thencentrifuged. The supernatant was subjected to ethanol precipitation inaccordance with the method described in Molecular Cloning, 2nd Edition,dried, and then redissolved in water. Restriction enzymes HindIII andEcoRI (manufactured by Takara Shuzo Co., Ltd.) were added to the DNAsolution and the DNA was digested. Agarose gel electrophoresis wassubsequently performed, thereby separating and purifying 2.0 kb DNAfragment. Plasmid vector pUC19 (manufactured by Takara Shuzo Co., Ltd.)was also digested with HindIII and EcoRI. 2.7 kb fragment was thenseparated and purified by agarose gel electrophoresis. 2.0 kb DNAfragment digested with HindIII and EcoRI was ligated to pUC19 usingLigation High and used to the transformation of Escherichia coli DH5a.As with (1) above, IPTG and X-gal were spread on the LB agar mediumcontaining 50 μg/ml ampicillin for the selection of the transformant.Several strains were selected among from the transformants obtained aswhite colonies and inoculated on 10 ml of LB medium containing 50 μg/mlampicillin and subjected to shaking culture at 37° C. for 16 hours.Thereafter, strains were harvested and plasmid DNA carried by eachstrain was extracted and purified by an alkaline method.

[0353] (3) Confirmation of Introduction of Nucleotide Substitution byNucleotide Sequencing

[0354] In nucleotide sequencing, ABI PRISM DNA Sequencing Kits-Dyeprimer Cycle Sequencing Ready Reaction Kits with AmpliTaqR DNAPolymerase, FS-21M13-(manufactured by PE Applied Biosystems), andABI373A were used. Each recombinant plasmid DNA, which is considered tohave nucleotide substitution introduced KS1 obtained in (2) above, wasused as templates and sequencing samples were produced by PCR inaccordance with the protocol attached to the Sequencing Kits. Eachsample was subjected to electrophoresis using ABI373A and the resultantdata was analyzed using a software for gene analysis, Genetyx(manufactured by Software Development Co., Ltd.). As a result, it wasconfirmed that plasmid DNA (pKS1mut) containing about 2.0 kb BamHIfragment corresponding to 1701 to 3716 in SEQ ID NO: 3 was obtained. SEQID NO: 3 comprises a nucleotide sequence in which thymine at the 1969position is substituted with guanine in the 1^(st) to 11916^(th)nucleotide sequences shown in SEQ ID NO: 1.

[0355] (4) Introduction of Nucleotide Substitution into Chromosomal DNAof Streptomyces avermitilis

[0356] In order to introduce the plasmid mutation into chromosomal DNAthrough homologous recombination, a reasonably long homologous region isnecessary. Since mutation is introduced into the DNA by PCR, mutationmay be introduced in the region other than the targeted site. Thus, thebroadest possible region other than the mutation site should besubstituted with DNA derived from chromosomal DNA of Streptomycesavermitilis to eliminate unnecessary mutation. Plasmid DNA used in thehomologous recombination was constructed in the following manner andapplied to the transformation of Streptomyces avermitilis.

[0357] pKS1mut produced in (3) above was digested with restrictionenzymes PstI and SalI (manufactured by Takara Shuzo Co., Ltd.) and thensubjected to agarose gel electrophoresis to separate and purify 4.1 kbDNA fragment. Subsequently, pKS1 was digested with PstI and SalI,followed by electrophoresis and 1.57 kb PstI and SalI digested fragmentswere separated and purified. Each collected DNA fragment was ligatedusing Ligation High and then brought into contact with a competent cellof Escherichia coli DH5α for transformation. The transformant wasselected using LB agar medium containing 50 μg/ml ampicillin.Transformants were cultured at 37° C. for 16 hours and ten-odd colonieswere collected with the aid of ase, inoculated on 10 ml of LB mediumcontaining 50 μg/ml ampicillin, subjected to shaking culture at 37° C.for 16 hours, harvested, and plasmid carried by each strain was purifiedby the alkaline method. Each plasmid was digested with restrictionenzymes PstI and SalI, subjected to agarose gel electrophoresis, and itwas confirmed that plasmid pKS1mutR containing 4.1 kb and 1.57 kb DNAfragments was obtained.

[0358] Subsequently, pKS1mutR was digested with restriction enzyme KpnI(manufactured by Takara Shuzo Co., Ltd.) and treated with alkalinephosphatase. Then, a cosmid, which contains a KpnI region represented bynucleotide 817 to 1887 shown in SEQ ID NO: 1, was digested with KpnI,followed by electrophoresis, and about 1.1 kb KpnI fragment wasseparated and purified. Each purified DNA fragment was ligated usingLigation High and then brought into contact with a competent cell ofEscherichia coli DH5α for transformation. The transformant was selectedusing the LB agar medium containing 50 μg/ml ampicillin. Transformantswere cultured at 37° C. for 16 hours and ten-odd colonies were collectedwith the aid of ase, inoculated on 10 ml of LB medium containing 50μg/ml ampicillin, subjected to shaking culture at 37° C. for 16 hours,harvested, and plasmid carried by each strain was purified by thealkaline method. Each plasmid was digested with restriction enzyme PstI,subjected to agarose gel electrophoresis, and it was confirmed thatplasmid pKS1mutRL containing 1.27 kb, 1.57 kb, and 2.7 kb DNA fragmentswas obtained.

[0359] Subsequently, pKS1mutRL was digested with restriction enzymesHindIII and EcoRI and 2.9 kb HindIII and EcoRI DNA fragments wereseparated and purified by agarose gel electrophoresis. Plasmid vectorpKC7 (Japanese Published Unexamined Patent Application No. 189774/94)was also digested with HindIII and EcoRI and then purified by agarosegel electrophoresis. These two DNA fragments were ligated at 16° C. for16 hours using Ligation High and then brought into contact with acompetent cell of Escherichia coli DH5α for transformation.Transformants were selected using the LB agar medium containing 50 μg/mlampicillin. Those transformants were cultured at 37° C. for 16 hours andten-odd colonies were collected with the aid of ase, and inoculated on10 ml of LB medium containing 50 μg/ml ampicillin. Those transformantswere cultured at 37° C. for 16 hours, and then cells were harvested andplasmid carried by each strain was purified by the alkaline method. Eachplasmid was digested with restriction enzymes HindIII and EcoRI and thensubjected to agarose gel electrophoresis. Thus, it was confirmed thatplasmid pKC-KS1mut carrying 2.9 kb fragment was obtained.

[0360] KS1mut fragment was integrated into the KS1 region of thechromosome of Streptomyces avermitilis K2038 (FERM BP-2775) byhomologous recombination using pKC-KS1mut in accordance with the methoddescribed in Japanese Published Unexamined Patent Application No.189774/94. In order to confirm that KS1mut was replaced on thechromosomal DNA, the chromosomal DNA of the thus obtained recombinantstrain was prepared by the method described in Japanese PublishedUnexamined Patent Application No. 189774/94, and PCR was carried outusing the chromosomal DNA as a template and using the synthetic DNAshown in SEQ ID NO: 10 (5′-ATAAGCTTAATCGATCCGCTGTCCGGTA-3′, containing asequence corresponding to nucleotides 1758 to 1776 in SEQ ID NO: 1) andthe synthetic DNA shown in SEQ ID NO: 11(5′-ATGAATTCCCTCCAAAATCACATGCGCATT-3′, containing a sequencecorresponding to nucleotides 2710 to 2729 in SEQ ID NO: 1) as a primerset. The about 1.0 kb amplified DNA fragment was digested withrestriction enzymes HindIII and EcoRI and about 1.0 kb amplifiedfragment was then separated and purified by agarose gel electrophoresis.Plasmid vector pUC19 was also digested with restriction enzymes HindIIIand EcoRI and then separated and purified by agarose gelelectrophoresis. The two DNA fragments thus obtained were ligated at 16°C. for 16 hours using Ligation High and then used to the transformationof Escherichia coli DH5α. IPTG and X-gal were spread on the LB agarmedium containing 50 μg/ml ampicillin for selecting the transformant.Several strains were selected among from the transformants, obtained aswhite colonies, and inoculated on 10 ml of LB medium containing 50 μg/mlampicillin. After the transformants were cultured by shaking, cells wereharvested and plasmid carried by each strain was extracted and purifiedby the alkaline method. The thus obtained plasmid was used to determinethe nucleotide sequence in the manner as described in (3) above. Thus,it was confirmed that the subject recombinant Streptomtces avermitilisKS1mut strain was obtained.

EXAMPLE 3 Synthesis of Substrate Compound

[0361] Physicochemical data of the following compounds were measuredusing the following instruments. MS JEOL. Ltd HX/HX110A ¹H NMR JEOL. LtdLambda 300 (300 MHz)

[0362] In the physical data of the compounds, “FABMS” indicates the massspectrum obtained by the “FAB” method. The term “conventionalpost-processing” refers to processing after the reaction.

[0363] After the completion of the reaction in each step, water, acids,buffers or the like is optionally added to the reaction solution toextract with a non-aqueous solvent such as ethyl acetate, ether,chloroform, and dichloromethane. The extract is washed with water, asaline solution, etc. and then dried over anhydrous sodium sulfate,thereby removing the solvent by distillation under reduced pressure.

[0364] (1) Synthesis of Compound 1

[0365] Compound A (16 g, 0.060 mol; Table 1) was dissolved in methanol(620 mL) and ozone-air current was blown at −78° C. while stirring for 4hours. After air was blown into the reaction solution for 15 minutes,dimethylsulfide (44 mL, 0.60 mol) was added thereto, and the mixture wasstirred at 25° C. for 15 hours. After the conventional post-processing,the residue was dissolved in toluene (290 mL), methyl(triphenylphosphoranylidene) acetate (33.7 g, 0.10 mol) was added, andthe mixture was stirred at 65° C. for 17 hours. After conventionalpost-processing, purification was carried out by chromatography onsilica gel (eluted at hexane/ethyl acetate=100/0 to 10/1) to giveCompound 1 (9.4 g, yield 53%; Table 1).

[0366]¹H NMR (CDCl₃) δ ppm; 7.04 (dd, J=8.3, 15.8 Hz, 1H), 5.78 (dd,J=1.1, 15.7 Hz, 1H), 3.72 (s, 3H), 3.48 (t, J=3.5 Hz, 1H), 2.52 (m, 1H),1.35-1.54 (m, 2H), 1.10 (m, 1H), 1.04 (d, J=7.0 Hz, 3H), 0.40 (s, 9H),0.37 (d, J=7.4 Hz, 3H), 0.35 (d, J=6.8 Hz, 3H), 0.03(s, 3H), 0.02 (s,3H)

[0367] FABMS: M/Z 315 (M+H)⁺

[0368] Molecular formula-based theoretical value: C₁₇H₃₄N₃Si=314

[0369] (2) Synthesis of Compound 2

[0370] Compound 1 (0.20 g, 0.63 mmol) was dissolved in methanol (8.9 mL)and 10% hydrogen chloride/methanol solution (0.99 mL) was added thereto,and the mixture was stirred at 50° C. for 1 hour. After conventionalpost-processing, the residue was dissolved in N,N-dimethylformamide (6.2mL), chlorotritylsilane (0.31 mL, 1.8 mmol) and imidazole (0.21 g, 3.1mmol) was added thereto, and the mixture was stirred at 25° C. for 1.5hours. After conventional post-processing, purification was carried outby chromatography on silica gel (eluted at hexane/ethyl acetate=25/1) togive Compound 2 (0.18 g, yield 93%; Table 1).

[0371]¹H NMR (CDCl₃) δ ppm; 7.04 (dd, J=8.4, 15.7 Hz, 1H), 5.79 (dd,J=1.1, 15.7 Hz, 1H), 3.73 (s, 3H), 3.48 (dd, J=4.1, 5.4 Hz, 1H), 2.51(m, 1H), 1.35-1.51 (m, 2H), 1.12 (m, 1H), 0.81-1.08 (m, 18H), 0.47-0.66(m, 6H)

[0372] FABMS: m/z 315 (M+H)⁺

[0373] Molecular formula-based theoretical value: C₁₇H₃₄N₃Si=314

[0374] (3) Synthesis of Compound 3

[0375] Compound 2 (4.1 g, 0.013 mol) was dissolved in ethanol (200 mL),10% palladium-carbon (0.41 g) was added thereto, and the mixture wasstirred under hydrogen atmosphere at 25° C. for 4.5 hours. After thereaction solution was passed through Celite R545, the solvent wasremoved by distillation under reduced pressure. The residue wasdissolved in 1,4-dioxane (100 mL) and water (100 mL), an aqueoussolution of 4 mol/l potassium hydroxide (6.4 mL, 0.026 mol) was addedthereto, and the mixture was stirred at 60° C. for 3.5 hours. DOWEX 50Wwas added to the reaction solution for neutralization and the solventwas then removed by distillation under reduced pressure. The residue wasdissolved in dichloromethane (200 mL), N-acetylcysteamine (1.8 mL, 0.017mol), hydrochloric acid/1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide(3.2 g, 0.017 mol), and 4-dimethylaminopyridine (0.32 g, 0.0026 mol)were added thereto, and the mixture was stirred at 25° C. for 11 hours.After conventional post-processing, purification was carried out bychromatography on silica gel (eluted at hexane/ethyl acetate=1/1) togive Compound 3 (3.8 g, yield 74%; Table 1).

[0376]¹H NMR (CDCl₃) δ ppm; 5.80 (br s, 1H), 3.43 (dd, J=6.1, 12.5 Hz,2H), 3.32 (dd, J=3.7, 5.3 Hz, 1H), 3.02 (t, J=6.6 Hz, 2H), 2.63 (dd,J=5.3, 9.9 Hz, 1H), 2.54 (dd, J=6.3, 9.4 Hz, 1H), 1.97 (s, 3H), 1.94 (m,1H), 1.58 (m, 1H), 1.31-1.54 (m, 3H), 1.16 (m, 1H), 0.81-1.00 (m, 18H),0.61 (q, J=7.6 Hz, 6H)

[0377] FABMS: m/z 404 (M+H)⁺

[0378] Molecular formula-based theoretical value: C₂₀H₄₁NO₃SiS=403

[0379] (4) Synthesis of Compound 4

[0380] Compound 3 (15 mg, 0.038 mmol) was dissolved in tetrahydrofuran(0.46 mL) and water (0.46 mL), acetic acid (0.45 mL) was added thereto,and the mixture was stirred at 0° C. for 2 hours. After conventionalpost-processing, purification was carried out by thin-layerchromatography (eluted at chloroform/methanol=10/1) to give Compound 4(7.7 mg, yield 71%, purity 63%; Table 1).

[0381]¹H NMR (CDCl₃) δ ppm; 5.88 (br s, 1H), 3.64 (dd, J=6.0, 12.3 Hz,2H), 3.20 (m, 1H), 3.02 (dt, J=1.8, 6.4 Hz, 2H), 2.58-2.72 (m, 2H), 2.06(m, 1H), 1.97 (s, 3H), 1.43-1.70 (m, 3H), 1.33 (m, 1H), 1.28 (m, 1H),0.82-0.95 (m, 9H)

[0382] FABMS: m/z 290 (M+H)⁺

[0383] Molecular formula-based theoretical value: C₁₄H₂₇NO₃S=289

EXAMPLE 4 Direct Production of 22,23-dihydroavermectin B1a

[0384] 10 μl of spore suspension of Streptomyces avermitilis KS1mutobtained in Example 2 was inoculated in a test tube containing 10 ml ofseed culture medium [a medium prepared by adjusting a solutioncontaining 20 g of lactose, 15 g of Distillers solubles, 2.5 g ofautolysed yeast (Difco), and 1,000 ml of distilled water at pH 7.2 with2 mol/l potassium hydroxide, followed by high pressure steamsterilization at 121° C. for 15 minutes] and was cultured by shaking at28° C. for 20 hours to obtain a seed culture. 0.4 ml of this seedculture was transferred to a conical flask (volume 100 ml) containing 20ml of production medium [a medium prepared by subjecting 46 g ofglucose, 24 g of peptonized milk (Oxoid), 2.5 g of autolysed yeast(Difco), 2.5 ml of polypropylene glycol #2000, and 1,000 ml of distilledwater to high pressure steam sterilization at 121° C. for 15 minutes]and was cultured using a rotary shaker at 28° C. for 3 days at 220 rpm,then 50 μl of 1 mg/ml methanol solution of Compound 4 synthesized inExample 3 (containing 50% Compound 4) was added to the culture, andculturing by shaking was carried out again at 28° C. for 2 days. Afterthe completion of culture, a double amount of methanol was added to theculture and the mixture was thoroughly stirred. Thereafter, the stirredproduct was centrifuged at room temperature at 3,000 rpm for 5 minutesto precipitate cells. The supernatant was then subjected tohigh-performance liquid chromatography (HPLC) analysis.

[0385] HPLC Analysis

[0386] Chromatography Condition Chromatography condition Column:Inertsil ODS-2 (4.6 × 150 mm, manufactured by GL Sciences Inc.) Guardcolumn: Guard column E cartridge (4 × 10 mm, manufactured by GL SciencesInc.) Mobile phase: acetonitrile:methanol:water = 70:10:20 Flow rate: 0.6 ml/min Detection: 246 nm Temperature: 55° C.

[0387] The methanol extract of the culture was analyzed under the aboveconditions for analysis and, as a result, a peak was observed at aretention time of 21.7 minutes only in the culture extract to whichCompound 4 was added. As a result of the analysis of22,23-dihydroavermectin B1a under the equivalent condition, theretention time was the same, i.e., 21.7 minutes. When22,23-dihydroavermectin B1a was determined as the standard, the yield ofthe substance exhibiting the retention time of 21.7 minutes, which wasobtained from the culture extract, was 23.3 mg/L.

[0388] Three-dimensional HPLC analysis was carried out using amulti-wavelength detector MD-915 (manufactured by Jasco) and, as aresult, the maximal absorption wavelength of the peak at the retentiontime of 21.7 minutes was 248 nm and the spectrum thereof coincided withthat of 22,23-dihydroavermectin B11 a.

[0389] The peak at the retention time of 21.7 minutes was fractionatedby HPLC and 5 mg of white powder was obtained and subjected to massspectometry. The results were as follows.

[0390] m/z 873.5 (M+) C₄₈H₇₃O₁₄

[0391] This coincided with data of 22,23-dihydroavermectin B1a describedin Ivermectin and Abamectin, William C. Campbell (1989).

[0392] As is apparent from the foregoing description, the substance,which was obtained by adding Compound 4 to Streptomyces avermitilisKS1mut and culturing the strain, was 22,23-dihydroavermectin B1a. In theabove culturing with addition of compound 4, avermectin analog otherthan 22,23-dihydroavermectin B1a was not produced at all. Since thesingle production of 22,23-dihydroavermectin B1a was realized, theproduction of 22,23-dihydroavermectin B1a was shown to have beensignificantly facilitated.

INDUSTRIAL APPLICABILITY

[0393] According to the present invention, 22,23-dihydroavermectin B1a,which is useful as a medicine, a veterinary drug, and a pesticide, canbe directly produced. Therefore, the conventional processes forpurifying avermectin B1a at an industrial level and for chemicallymodifying avermectin B1a, which are complicated and difficult, can beomitted. This can significantly decrease the cost and the time for theindustrial production of 22,23-dihydroavermectin B1a. This also realizesthe production of the formulation containing only22,23-dihydroavermectin B1a, which is highly effective as medicines.

[0394] [Sequence Listing Free Text]

[0395] SEQ ID NO: 9 represents synthetic DNA based on the sequencebetween nucleotides 1954 and 1985 shown in SEQ ID NO: 1

[0396] SEQ ID NO: 10 represents synthetic DNA based on the sequencebetween nucleotides 1758 and 1776 shown in SEQ ID NO: 1

[0397] SEQ ID NO: 11 represents synthetic DNA based on the sequencebetween nucleotides 2710 and 2729 in SEQ ID NO: 1

1 11 1 30690 DNA Streptomyces avermitilis CDS (1)..(11916) CDS(11971)..(30687) 1 gtg cag agg atg gac ggc ggg gaa gaa ccc cgc cct gcggca ggg gag 48 Val Gln Arg Met Asp Gly Gly Glu Glu Pro Arg Pro Ala AlaGly Glu 1 5 10 15 gtc ctc gga gtg gcc gac gag gcg gac ggc ggc gtc gtcttc gtt ttt 96 Val Leu Gly Val Ala Asp Glu Ala Asp Gly Gly Val Val PheVal Phe 20 25 30 ccc ggg cag ggc ccg caa tgg ccg ggc atg gga agg gaa cttctc gac 144 Pro Gly Gln Gly Pro Gln Trp Pro Gly Met Gly Arg Glu Leu LeuAsp 35 40 45 gct tcc gac gtc ttc cgg gag agc gtc cgc gcc tgc gaa gcc gcgttc 192 Ala Ser Asp Val Phe Arg Glu Ser Val Arg Ala Cys Glu Ala Ala Phe50 55 60 gcg ccc tac gtc gac tgg tcg gtg gag cag gtg ttg cgg gac tcg ccg240 Ala Pro Tyr Val Asp Trp Ser Val Glu Gln Val Leu Arg Asp Ser Pro 6570 75 80 gac gct ccc ggg ctg gac cgg gtg gac gtc gtc cag ccg acc ctg ttc288 Asp Ala Pro Gly Leu Asp Arg Val Asp Val Val Gln Pro Thr Leu Phe 8590 95 gcc gtc atg atc tcc ctg gcc gcc ctc tgg cgc tcg caa ggg gtc gag336 Ala Val Met Ile Ser Leu Ala Ala Leu Trp Arg Ser Gln Gly Val Glu 100105 110 ccg tgc gcg gtg ctg gga cac agc ctg ggc gag atc gcg gca gcc cac384 Pro Cys Ala Val Leu Gly His Ser Leu Gly Glu Ile Ala Ala Ala His 115120 125 gtc tcg gga ggc ctg tcc ctg gcc gac gcc gca cgc gtg gtg acg ctt432 Val Ser Gly Gly Leu Ser Leu Ala Asp Ala Ala Arg Val Val Thr Leu 130135 140 tgg agc cag gca cag acc acc ctt gcc ggg acc ggc gcg ctc gtc tcc480 Trp Ser Gln Ala Gln Thr Thr Leu Ala Gly Thr Gly Ala Leu Val Ser 145150 155 160 gtc gcc gcc acg ccg gat gag ctc ctg ccc cga atc gct ccg tggacc 528 Val Ala Ala Thr Pro Asp Glu Leu Leu Pro Arg Ile Ala Pro Trp Thr165 170 175 gag gac aac ccg gcg cgg ctc gcc gtc gca gcc gtc aac gga ccccgg 576 Glu Asp Asn Pro Ala Arg Leu Ala Val Ala Ala Val Asn Gly Pro Arg180 185 190 agc aca gtc gtt tcc ggt gcc cgc gag gcc gtc gcg gac ctg gtggcc 624 Ser Thr Val Val Ser Gly Ala Arg Glu Ala Val Ala Asp Leu Val Ala195 200 205 gac ctc acc gcc gcg cag gtg cgc acg cgc atg atc ccg gtg gacgtt 672 Asp Leu Thr Ala Ala Gln Val Arg Thr Arg Met Ile Pro Val Asp Val210 215 220 ccc gcc cac tcc ccc ctg atg tac gcc atc gag gaa cgg gtc gtcagc 720 Pro Ala His Ser Pro Leu Met Tyr Ala Ile Glu Glu Arg Val Val Ser225 230 235 240 ggc ctg ctg ccc atc acc cca cgc ccc tcc cgc atc ccc ttccac tcc 768 Gly Leu Leu Pro Ile Thr Pro Arg Pro Ser Arg Ile Pro Phe HisSer 245 250 255 tcg gtg acc ggc ggc cgc ctc gac acc cgc gag cta gac gcggcg tac 816 Ser Val Thr Gly Gly Arg Leu Asp Thr Arg Glu Leu Asp Ala AlaTyr 260 265 270 tgg tac cgc aac atg tcg agc acg gtc cgg ttc gag ccc gccgcc cgg 864 Trp Tyr Arg Asn Met Ser Ser Thr Val Arg Phe Glu Pro Ala AlaArg 275 280 285 ctg ctt ctg cag cag ggg ccc aag acg ttc gtc gag atg agcccg cac 912 Leu Leu Leu Gln Gln Gly Pro Lys Thr Phe Val Glu Met Ser ProHis 290 295 300 ccg gtg ctg acc atg ggc ctc cag gag ctc gcc ccg gac ctgggc gac 960 Pro Val Leu Thr Met Gly Leu Gln Glu Leu Ala Pro Asp Leu GlyAsp 305 310 315 320 acc acc ggc acc gcc gac acc gtg atc atg ggc acg ctgcgc cgc ggc 1008 Thr Thr Gly Thr Ala Asp Thr Val Ile Met Gly Thr Leu ArgArg Gly 325 330 335 cag ggc acc ctg gac cac ttc ctg acg tct ctc gcc caacta cgg ggg 1056 Gln Gly Thr Leu Asp His Phe Leu Thr Ser Leu Ala Gln LeuArg Gly 340 345 350 cat ggt gag acg tcg gcg acc acc gtc ctc tcg gca cgcctg acc gcg 1104 His Gly Glu Thr Ser Ala Thr Thr Val Leu Ser Ala Arg LeuThr Ala 355 360 365 ctg tcc ccc acg cag cag cag tcg ctg ctc ctg gac ctggtg cgc gcc 1152 Leu Ser Pro Thr Gln Gln Gln Ser Leu Leu Leu Asp Leu ValArg Ala 370 375 380 cac acc atg gcg gtg ctg aac gac gac gga aac gag cgcacc gcg tcg 1200 His Thr Met Ala Val Leu Asn Asp Asp Gly Asn Glu Arg ThrAla Ser 385 390 395 400 gat gcc ggc cca tcg gcg agt ttc gcc cac ctc ggcttc gac tcc gtc 1248 Asp Ala Gly Pro Ser Ala Ser Phe Ala His Leu Gly PheAsp Ser Val 405 410 415 atg ggt gtc gaa ctg cgc aac cgc ctc agc aag gccacg ggc ctg cgg 1296 Met Gly Val Glu Leu Arg Asn Arg Leu Ser Lys Ala ThrGly Leu Arg 420 425 430 ttg ccc gtg acg ctc atc ttc gac cac acc acg ccggcc gcg gtc gcc 1344 Leu Pro Val Thr Leu Ile Phe Asp His Thr Thr Pro AlaAla Val Ala 435 440 445 gcg cgc ctt cgg acc gcg gcg ctc ggc cac ctc gacgag gac acc gcg 1392 Ala Arg Leu Arg Thr Ala Ala Leu Gly His Leu Asp GluAsp Thr Ala 450 455 460 ccc gta ccg gac tca ccc agc ggc cac gga ggc acggca gcg gcg gac 1440 Pro Val Pro Asp Ser Pro Ser Gly His Gly Gly Thr AlaAla Ala Asp 465 470 475 480 gac ccg atc gcc atc atc ggc atg gca tgc cgtttc ccg ggc gga gtc 1488 Asp Pro Ile Ala Ile Ile Gly Met Ala Cys Arg PhePro Gly Gly Val 485 490 495 cgg tcc ccg aag gac ctg tgg gag ctg gcc gcctcg ggc gga gac gcc 1536 Arg Ser Pro Lys Asp Leu Trp Glu Leu Ala Ala SerGly Gly Asp Ala 500 505 510 atc ggg ccg ttc ccc acc gac cgc gga tgg cccacg gaa cag cgt cac 1584 Ile Gly Pro Phe Pro Thr Asp Arg Gly Trp Pro ThrGlu Gln Arg His 515 520 525 gcc cag gac ccc acg cag ccc ggc acg ttc tatccg cag gga ggc ggg 1632 Ala Gln Asp Pro Thr Gln Pro Gly Thr Phe Tyr ProGln Gly Gly Gly 530 535 540 ttc ctt cac gac gcg gcg cac ttc gac gcc ggcttc ttc gga atc agt 1680 Phe Leu His Asp Ala Ala His Phe Asp Ala Gly PhePhe Gly Ile Ser 545 550 555 560 cca cgt gag gca ctg gcg atg gat ccg cagcag cgg ctg ctg ctg gag 1728 Pro Arg Glu Ala Leu Ala Met Asp Pro Gln GlnArg Leu Leu Leu Glu 565 570 575 acg tcc tgg gag gcg ttc gag cgg gcg ggaatc gat ccg ctg tcg gta 1776 Thr Ser Trp Glu Ala Phe Glu Arg Ala Gly IleAsp Pro Leu Ser Val 580 585 590 cgc ggg tcc cgt acg ggc gtc ttc gcg ggcgcc ctc tcc ttc gac tac 1824 Arg Gly Ser Arg Thr Gly Val Phe Ala Gly AlaLeu Ser Phe Asp Tyr 595 600 605 ggc ccg cgt atg gac acc gcg tcg tcg gagggc gcc gcg gac gtg gag 1872 Gly Pro Arg Met Asp Thr Ala Ser Ser Glu GlyAla Ala Asp Val Glu 610 615 620 ggc cac atc ctc acc ggt acc acg ggc agcgtc ctg tcg ggc cgt atc 1920 Gly His Ile Leu Thr Gly Thr Thr Gly Ser ValLeu Ser Gly Arg Ile 625 630 635 640 gcc tac agc ttc ggg ctg gaa ggg ccggcg atc acc gtg gac acg ggg 1968 Ala Tyr Ser Phe Gly Leu Glu Gly Pro AlaIle Thr Val Asp Thr Gly 645 650 655 tgc tcg gca tcg ctc gtg acg ctg catctg gcg tgc cag tcg ctg cgg 2016 Cys Ser Ala Ser Leu Val Thr Leu His LeuAla Cys Gln Ser Leu Arg 660 665 670 tcg ggt gag tgc acg ctc gcg ctg gccggc ggc gtc tcg gtc atg tcc 2064 Ser Gly Glu Cys Thr Leu Ala Leu Ala GlyGly Val Ser Val Met Ser 675 680 685 acc ctc ggc atg ttc atc gag ttc tcccgg cag cgc ggg ctg tcg gtg 2112 Thr Leu Gly Met Phe Ile Glu Phe Ser ArgGln Arg Gly Leu Ser Val 690 695 700 gac ggc agg tgc aag gcg tac tcg gctgca gcc gac ggc acc ggc tgg 2160 Asp Gly Arg Cys Lys Ala Tyr Ser Ala AlaAla Asp Gly Thr Gly Trp 705 710 715 720 ggc gag ggc gtc ggg atg ctg ttggtg gag cgg ttg tcg gat gcg gtg 2208 Gly Glu Gly Val Gly Met Leu Leu ValGlu Arg Leu Ser Asp Ala Val 725 730 735 cgg ctg ggg cat cgg gtg ctg gcggtg gta cgc ggc agt gcg gtc aac 2256 Arg Leu Gly His Arg Val Leu Ala ValVal Arg Gly Ser Ala Val Asn 740 745 750 cag gac ggt gcg tcg aat ggg ctgacg gcg ccg aac ggt ccg gct cag 2304 Gln Asp Gly Ala Ser Asn Gly Leu ThrAla Pro Asn Gly Pro Ala Gln 755 760 765 gag cgg gtg atc cgg cag gcg ttggcg aac gcg ggg ttg tcc gtg gcg 2352 Glu Arg Val Ile Arg Gln Ala Leu AlaAsn Ala Gly Leu Ser Val Ala 770 775 780 gat gtg gat gtg gtg gag ggg cacggg acg ggc acg acg ctg ggt gat 2400 Asp Val Asp Val Val Glu Gly His GlyThr Gly Thr Thr Leu Gly Asp 785 790 795 800 ccg atc gag gca cag gcg ttgctc gcc acg tac ggg cag cgg gcc ggt 2448 Pro Ile Glu Ala Gln Ala Leu LeuAla Thr Tyr Gly Gln Arg Ala Gly 805 810 815 gac agg ccg ctg tgg ctg gggtct ctg aag tcc aac atc ggg cac acc 2496 Asp Arg Pro Leu Trp Leu Gly SerLeu Lys Ser Asn Ile Gly His Thr 820 825 830 atg gct gcc gcg ggt gtg ggtggg gtc atc aag atg gtg atg gcg ttg 2544 Met Ala Ala Ala Gly Val Gly GlyVal Ile Lys Met Val Met Ala Leu 835 840 845 cgg gag ggg gtg ttg ccg cggacg ttg cat gtg gat aag ccg tcg ccg 2592 Arg Glu Gly Val Leu Pro Arg ThrLeu His Val Asp Lys Pro Ser Pro 850 855 860 cag gtg gac tgg tcc gcg ggggcg gtg cgg ctg ctg acg gag gcg gtg 2640 Gln Val Asp Trp Ser Ala Gly AlaVal Arg Leu Leu Thr Glu Ala Val 865 870 875 880 ccg tgg ccg ggg gac gcggca ggg cgg ttg cgg cgg gcg gga gtg tcg 2688 Pro Trp Pro Gly Asp Ala AlaGly Arg Leu Arg Arg Ala Gly Val Ser 885 890 895 tcg ttc ggg atc ggc ggcacg aat gcg cat gtg att ttg gag gag gcg 2736 Ser Phe Gly Ile Gly Gly ThrAsn Ala His Val Ile Leu Glu Glu Ala 900 905 910 ccg gcg gcg ggg ggc tgtgtt gcc ggg ggt ggg gtg ttg gag ggt gct 2784 Pro Ala Ala Gly Gly Cys ValAla Gly Gly Gly Val Leu Glu Gly Ala 915 920 925 ccg ggt ctt gcc att tcggtg gct gag tcg gtg gcc gct cca gtg gct 2832 Pro Gly Leu Ala Ile Ser ValAla Glu Ser Val Ala Ala Pro Val Ala 930 935 940 gtg tct gcg ccg gtg gctgag tcg gtg ccg gtg ccg gtg ccg gtg ccg 2880 Val Ser Ala Pro Val Ala GluSer Val Pro Val Pro Val Pro Val Pro 945 950 955 960 gtt cct gtg ccg gtgtcg gct agg tct gag gct ggg ttg cgg gcg cag 2928 Val Pro Val Pro Val SerAla Arg Ser Glu Ala Gly Leu Arg Ala Gln 965 970 975 gcg gag gcg ttg cgtcag tac gtg gca gtc cgg ccg gac gtt tcg ctt 2976 Ala Glu Ala Leu Arg GlnTyr Val Ala Val Arg Pro Asp Val Ser Leu 980 985 990 gcc gat gtg ggt gcgggt ctg gcc tgt ggg cgg gct gtg ctg gag cat 3024 Ala Asp Val Gly Ala GlyLeu Ala Cys Gly Arg Ala Val Leu Glu His 995 1000 1005 cgt gcg gtc gtcctg gcc gcg gac cgt gag gag ctg gtg caa ggg ttg 3072 Arg Ala Val Val LeuAla Ala Asp Arg Glu Glu Leu Val Gln Gly Leu 1010 1015 1020 ggg gcg ctggcg gcg ggt gag ccg gat cgg cgg gtg acc acg ggt cat 3120 Gly Ala Leu AlaAla Gly Glu Pro Asp Arg Arg Val Thr Thr Gly His 1025 1030 1035 1040 gcgccg ggt ggt gac cgg ggc ggt gtc gtc ttc gtg ttt ccc gga cag 3168 Ala ProGly Gly Asp Arg Gly Gly Val Val Phe Val Phe Pro Gly Gln 1045 1050 1055ggt ggg cag tgg gcc ggg atg ggt gtg cgt ctg ctc gcc tcc tct ccg 3216 GlyGly Gln Trp Ala Gly Met Gly Val Arg Leu Leu Ala Ser Ser Pro 1060 10651070 gtg ttc gcc cgg cgg atg cag gcg tgc gag gag gct ctg gcg ccg tgg3264 Val Phe Ala Arg Arg Met Gln Ala Cys Glu Glu Ala Leu Ala Pro Trp1075 1080 1085 gtg gac tgg tct gtg gtg gac atc ctg cgc cgg gac gcg ggggat gcg 3312 Val Asp Trp Ser Val Val Asp Ile Leu Arg Arg Asp Ala Gly AspAla 1090 1095 1100 gtg tgg gag cgg gcc gat gtg gtc cag cct gtg ctg ttcagc gtc atg 3360 Val Trp Glu Arg Ala Asp Val Val Gln Pro Val Leu Phe SerVal Met 1105 1110 1115 1120 gtg tct ttg gct gct ctg tgg cgt tcc tac ggtatc gaa ccc gac gcg 3408 Val Ser Leu Ala Ala Leu Trp Arg Ser Tyr Gly IleGlu Pro Asp Ala 1125 1130 1135 gtc ctt ggc cat tcc cag ggc gag atc gcggcc gcg cat gtg tgt ggg 3456 Val Leu Gly His Ser Gln Gly Glu Ile Ala AlaAla His Val Cys Gly 1140 1145 1150 gcg ctg agc ctg aag gac gcg gcg aagact gtt gcg ctg cgc agc cgg 3504 Ala Leu Ser Leu Lys Asp Ala Ala Lys ThrVal Ala Leu Arg Ser Arg 1155 1160 1165 gcg ctg gcc gct gtg cgg ggc cggggc ggc atg gcc tca gtg ccg ctg 3552 Ala Leu Ala Ala Val Arg Gly Arg GlyGly Met Ala Ser Val Pro Leu 1170 1175 1180 cct gcc cag gag gtg gag cagctc att ggt gag cgg tgg gcg ggg cgg 3600 Pro Ala Gln Glu Val Glu Gln LeuIle Gly Glu Arg Trp Ala Gly Arg 1185 1190 1195 1200 ttg tgg gtg gcg gcggtc aac ggc ccc cgc tcc acc gcc gtc tcg ggg 3648 Leu Trp Val Ala Ala ValAsn Gly Pro Arg Ser Thr Ala Val Ser Gly 1205 1210 1215 gat gcc gag gcggtg gac gag gtg ctg gcg tac tgt gcc ggc acc ggg 3696 Asp Ala Glu Ala ValAsp Glu Val Leu Ala Tyr Cys Ala Gly Thr Gly 1220 1225 1230 gtg cgg gcccgg cgg atc ccg gtc gac tat gcc tcg cac tgc ccc cat 3744 Val Arg Ala ArgArg Ile Pro Val Asp Tyr Ala Ser His Cys Pro His 1235 1240 1245 gtg cagccc ctg cgg gag gag ttg ctg gag ctg ctg ggg gac atc agc 3792 Val Gln ProLeu Arg Glu Glu Leu Leu Glu Leu Leu Gly Asp Ile Ser 1250 1255 1260 ccgcag ccg tcc ggc gtg ccg ttc ttc tcc acg gtg gag ggc acc tgg 3840 Pro GlnPro Ser Gly Val Pro Phe Phe Ser Thr Val Glu Gly Thr Trp 1265 1270 12751280 ctg gac acc aca acc ctg gac gcc gcc tac tgg tac cgc aac ctg cac3888 Leu Asp Thr Thr Thr Leu Asp Ala Ala Tyr Trp Tyr Arg Asn Leu His1285 1290 1295 cag ccg gtc cgt ttc agc gat gcc gtc cag gcc ctg gcg gatgac gga 3936 Gln Pro Val Arg Phe Ser Asp Ala Val Gln Ala Leu Ala Asp AspGly 1300 1305 1310 cac cgc gtc ttc gtc gaa gtc agc ccc cac ccc acc ctcgtc ccc gcc 3984 His Arg Val Phe Val Glu Val Ser Pro His Pro Thr Leu ValPro Ala 1315 1320 1325 atc gaa gac acc acc gaa gac acc gcc gaa gac gtcacc gcg atc ggc 4032 Ile Glu Asp Thr Thr Glu Asp Thr Ala Glu Asp Val ThrAla Ile Gly 1330 1335 1340 agc ctc cgc cgc ggc gac aac gac acc cgc cgcttc ctc acc gcc ctc 4080 Ser Leu Arg Arg Gly Asp Asn Asp Thr Arg Arg PheLeu Thr Ala Leu 1345 1350 1355 1360 gcc cac acc cat acc acc ggc atc ggcaca ccc acc acc tgg cac cac 4128 Ala His Thr His Thr Thr Gly Ile Gly ThrPro Thr Thr Trp His His 1365 1370 1375 cac tac acc cac cac cac acc cacccc cac ccc cac acg cac ctc gac 4176 His Tyr Thr His His His Thr His ProHis Pro His Thr His Leu Asp 1380 1385 1390 ctg ccc acc tac ccc ttc caacac cag cac tac tgg ctc gag agc tca 4224 Leu Pro Thr Tyr Pro Phe Gln HisGln His Tyr Trp Leu Glu Ser Ser 1395 1400 1405 cag ccg ggt gcc gga tccggt tcg ggt gcc ggt gcc ggt tcg ggt gcc 4272 Gln Pro Gly Ala Gly Ser GlySer Gly Ala Gly Ala Gly Ser Gly Ala 1410 1415 1420 ggt tcc ggg cgg gcaggg act gcg ggc ggg acg gca gag gtg gag tcg 4320 Gly Ser Gly Arg Ala GlyThr Ala Gly Gly Thr Ala Glu Val Glu Ser 1425 1430 1435 1440 cgg ttc tgggac gcg gtg gcc cgc cag gac ctg gaa acg gtc gcg acc 4368 Arg Phe Trp AspAla Val Ala Arg Gln Asp Leu Glu Thr Val Ala Thr 1445 1450 1455 aca ctcgcc gtg ccc ccc tcc gcc ggc ctg gac acg gtg gtg ccc gca 4416 Thr Leu AlaVal Pro Pro Ser Ala Gly Leu Asp Thr Val Val Pro Ala 1460 1465 1470 ctctcc gcc tgg cac cgc cac caa cac gac caa gcc cgc atc aac acc 4464 Leu SerAla Trp His Arg His Gln His Asp Gln Ala Arg Ile Asn Thr 1475 1480 1485tgg acc tac cag gaa acc tgg aaa ccc ctc acc ctc ccc acc acc cac 4512 TrpThr Tyr Gln Glu Thr Trp Lys Pro Leu Thr Leu Pro Thr Thr His 1490 14951500 caa ccc cac caa acc tgg ctc atc gcc atc ccc gaa acc cag acc cac4560 Gln Pro His Gln Thr Trp Leu Ile Ala Ile Pro Glu Thr Gln Thr His1505 1510 1515 1520 cac ccc cac atc acc aac atc ctc acc aac ctc cac caccac ggc atc 4608 His Pro His Ile Thr Asn Ile Leu Thr Asn Leu His His HisGly Ile 1525 1530 1535 acc ccc atc ccc ctc acc ctc aac cac acc cac accaac ccc caa cac 4656 Thr Pro Ile Pro Leu Thr Leu Asn His Thr His Thr AsnPro Gln His 1540 1545 1550 ctc cac cac acc ctc cac cac acc cga caa caagcc caa aac cac acc 4704 Leu His His Thr Leu His His Thr Arg Gln Gln AlaGln Asn His Thr 1555 1560 1565 acc gga gcc atc acc ggc ctg ctc tcc ctcctc gcc ctc gac gaa aca 4752 Thr Gly Ala Ile Thr Gly Leu Leu Ser Leu LeuAla Leu Asp Glu Thr 1570 1575 1580 ccc cac ccc cac cac ccc cac aca cccacc ggc acc ctc ctc aac ctc 4800 Pro His Pro His His Pro His Thr Pro ThrGly Thr Leu Leu Asn Leu 1585 1590 1595 1600 acc ctc acc caa acc cac acccaa acc cac cca cca acc ccc ctc tgg 4848 Thr Leu Thr Gln Thr His Thr GlnThr His Pro Pro Thr Pro Leu Trp 1605 1610 1615 tac gcc acc acc aac gccacc acc acc cac ccc aac gac ccc ctc aca 4896 Tyr Ala Thr Thr Asn Ala ThrThr Thr His Pro Asn Asp Pro Leu Thr 1620 1625 1630 cac ccc acc caa gcccaa acc tgg gga ctc gcc cgc acc acc ctc ctc 4944 His Pro Thr Gln Ala GlnThr Trp Gly Leu Ala Arg Thr Thr Leu Leu 1635 1640 1645 gaa cac ccc acccac acc gcc gga atc atc gac ctc ccc acc acc ccc 4992 Glu His Pro Thr HisThr Ala Gly Ile Ile Asp Leu Pro Thr Thr Pro 1650 1655 1660 acc ccc cacacc ctc cag cac ctc acc caa acc ctc acc caa ccc cac 5040 Thr Pro His ThrLeu Gln His Leu Thr Gln Thr Leu Thr Gln Pro His 1665 1670 1675 1680 caccaa acc caa ctc gcc atc cgc acc acc ggc acc cac acc cgc cgc 5088 His GlnThr Gln Leu Ala Ile Arg Thr Thr Gly Thr His Thr Arg Arg 1685 1690 1695ctc acc ccc acc acc ctc acc ccc aca cac caa cca ccc acc ccc acc 5136 LeuThr Pro Thr Thr Leu Thr Pro Thr His Gln Pro Pro Thr Pro Thr 1700 17051710 ccc cac gga acc acc ctc atc acc ggc gga acc ggc gcc ctc gcc acc5184 Pro His Gly Thr Thr Leu Ile Thr Gly Gly Thr Gly Ala Leu Ala Thr1715 1720 1725 cac ctc acc cac cac ctc acc acc cac caa ccc acc caa cacctc ctc 5232 His Leu Thr His His Leu Thr Thr His Gln Pro Thr Gln His LeuLeu 1730 1735 1740 ctc acc agc cga acc ggc ccc cac acc ccc cac gca caacac ctc acc 5280 Leu Thr Ser Arg Thr Gly Pro His Thr Pro His Ala Gln HisLeu Thr 1745 1750 1755 1760 acc caa ctc caa caa aaa ggc atc cac ctc accatc acc acc tgc gac 5328 Thr Gln Leu Gln Gln Lys Gly Ile His Leu Thr IleThr Thr Cys Asp 1765 1770 1775 acc agc aac cca gac caa ctc caa caa ctcctc aac acc atc ccc cca 5376 Thr Ser Asn Pro Asp Gln Leu Gln Gln Leu LeuAsn Thr Ile Pro Pro 1780 1785 1790 caa cac ccc ctc acc acc gtc atc cacacc gca ggc atc ctc gac gac 5424 Gln His Pro Leu Thr Thr Val Ile His ThrAla Gly Ile Leu Asp Asp 1795 1800 1805 gcc acc ctc acc aac ctc acc cccacc caa ctc aac aac gtc ctc cgc 5472 Ala Thr Leu Thr Asn Leu Thr Pro ThrGln Leu Asn Asn Val Leu Arg 1810 1815 1820 gcc aaa gcc cac agc gcc cacctc ctc cac caa ctc acc caa cac acc 5520 Ala Lys Ala His Ser Ala His LeuLeu His Gln Leu Thr Gln His Thr 1825 1830 1835 1840 ccc ctc acc gcc ttcgtc ctc tac tcc tcc gcc gcc gcc acc ttc ggc 5568 Pro Leu Thr Ala Phe ValLeu Tyr Ser Ser Ala Ala Ala Thr Phe Gly 1845 1850 1855 gca ccc ggc caagcc aac tac gcc gca gcc aac gcc tac ctc gac gcc 5616 Ala Pro Gly Gln AlaAsn Tyr Ala Ala Ala Asn Ala Tyr Leu Asp Ala 1860 1865 1870 ctc gcc caccac cgc cac acc cac cac ctc ccc gcc acc agc atc gcc 5664 Leu Ala His HisArg His Thr His His Leu Pro Ala Thr Ser Ile Ala 1875 1880 1885 tgg ggcacc tgg caa gga aac gga ctc gct gat tcg gac aag gcc cgc 5712 Trp Gly ThrTrp Gln Gly Asn Gly Leu Ala Asp Ser Asp Lys Ala Arg 1890 1895 1900 gcatat ctc gac cgc cgc ggg ttt cga ccc atg tca ccc gag ttg gcc 5760 Ala TyrLeu Asp Arg Arg Gly Phe Arg Pro Met Ser Pro Glu Leu Ala 1905 1910 19151920 acg gca gcg gtc acg cag gcg atc gcg gac acc gaa cgg ccg tat gtc5808 Thr Ala Ala Val Thr Gln Ala Ile Ala Asp Thr Glu Arg Pro Tyr Val1925 1930 1935 gtc atc gcc gac atc gac tgg agc aag atc gaa cac acc tctcag acc 5856 Val Ile Ala Asp Ile Asp Trp Ser Lys Ile Glu His Thr Ser GlnThr 1940 1945 1950 agc gac ctg gtg agc gcg gcc cgg gaa agg gag cca gctgtc cag cgc 5904 Ser Asp Leu Val Ser Ala Ala Arg Glu Arg Glu Pro Ala ValGln Arg 1955 1960 1965 ccc act cca ccg gcg gag ttg cac aaa acg ctg gcccat cag acg tcg 5952 Pro Thr Pro Pro Ala Glu Leu His Lys Thr Leu Ala HisGln Thr Ser 1970 1975 1980 gcc gac caa cgg gcc gca ttg ctc gag ctc gtacga gac cat gtg gcg 6000 Ala Asp Gln Arg Ala Ala Leu Leu Glu Leu Val ArgAsp His Val Ala 1985 1990 1995 2000 gca gtg ctc cgg cac gcg gac ccg aaagcc atc gcg ccc gac cag tcg 6048 Ala Val Leu Arg His Ala Asp Pro Lys AlaIle Ala Pro Asp Gln Ser 2005 2010 2015 ttc cgt gca ctc ggc ttc gat tcactc acg gcc gtc gag ttc cga aac 6096 Phe Arg Ala Leu Gly Phe Asp Ser LeuThr Ala Val Glu Phe Arg Asn 2020 2025 2030 ctg ctg atc aag gca aca ggactc cgc ctt cct gtc tcg ctg gtc ttc 6144 Leu Leu Ile Lys Ala Thr Gly LeuArg Leu Pro Val Ser Leu Val Phe 2035 2040 2045 gac cac ccg acc cct gccaaa ctc gcc gta cac ctg cag aac caa ctg 6192 Asp His Pro Thr Pro Ala LysLeu Ala Val His Leu Gln Asn Gln Leu 2050 2055 2060 cgg ggc aca gca gcggag tcg gct cct tca gcg gca gcc gtt acc gcc 6240 Arg Gly Thr Ala Ala GluSer Ala Pro Ser Ala Ala Ala Val Thr Ala 2065 2070 2075 2080 gag gct tctgtc acc gag ccg atc gcc atc gtt ggc atg gcc tgt cgt 6288 Glu Ala Ser ValThr Glu Pro Ile Ala Ile Val Gly Met Ala Cys Arg 2085 2090 2095 ttc cccggc gga gtg acc tcg gcg gac gac ttc tgg gat ctg atc tcc 6336 Phe Pro GlyGly Val Thr Ser Ala Asp Asp Phe Trp Asp Leu Ile Ser 2100 2105 2110 tccgag cag gac gcg atc ggc gga ttc ccc acc gac cgc ggc tgg gac 6384 Ser GluGln Asp Ala Ile Gly Gly Phe Pro Thr Asp Arg Gly Trp Asp 2115 2120 2125ctg gac acg ctc tac gac ccc gac ccc gac cac ccc ggc acc tgc tac 6432 LeuAsp Thr Leu Tyr Asp Pro Asp Pro Asp His Pro Gly Thr Cys Tyr 2130 21352140 acc cga aac ggc gga ttc ctc tac gac gca ggc cac ttc gac gcc gaa6480 Thr Arg Asn Gly Gly Phe Leu Tyr Asp Ala Gly His Phe Asp Ala Glu2145 2150 2155 2160 ttc ttc ggc atc agc ccc cgc gaa gcc ctc gcc atg gacccc cag caa 6528 Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu Ala Met Asp ProGln Gln 2165 2170 2175 cga ctc ctc ctc gaa acc gcc tgg gaa acc atc gaacac gcc ggc atc 6576 Arg Leu Leu Leu Glu Thr Ala Trp Glu Thr Ile Glu HisAla Gly Ile 2180 2185 2190 aac ccc cac acc ctc cac ggc acc ccc acc ggagtc ttc acc ggc acc 6624 Asn Pro His Thr Leu His Gly Thr Pro Thr Gly ValPhe Thr Gly Thr 2195 2200 2205 aac gga cag gac tac gca ctt cgc gtg cacaac gcg ggc cag tca acc 6672 Asn Gly Gln Asp Tyr Ala Leu Arg Val His AsnAla Gly Gln Ser Thr 2210 2215 2220 gat ggt ttc gca ctg acc gga acc gccggc agc gtc atc tcc ggt cgt 6720 Asp Gly Phe Ala Leu Thr Gly Thr Ala GlySer Val Ile Ser Gly Arg 2225 2230 2235 2240 atc tcg tac acg ttt ggt tttgag ggt cct gcg gtg tcg gtg gac acg 6768 Ile Ser Tyr Thr Phe Gly Phe GluGly Pro Ala Val Ser Val Asp Thr 2245 2250 2255 gct tgt tcc tcg tcg ttggtg gct ttg cat ctg gcc tgt cag gcg ttg 6816 Ala Cys Ser Ser Ser Leu ValAla Leu His Leu Ala Cys Gln Ala Leu 2260 2265 2270 cgt gcg ggt gag tgctcg atg gcg ctt gcc ggg ggt gtg acg gtg atg 6864 Arg Ala Gly Glu Cys SerMet Ala Leu Ala Gly Gly Val Thr Val Met 2275 2280 2285 tcg tct ccg ggtgcc ttc gtg gag ttt tcg cgg cag cgg ggt ctg gcc 6912 Ser Ser Pro Gly AlaPhe Val Glu Phe Ser Arg Gln Arg Gly Leu Ala 2290 2295 2300 gcg gac gggcat tgc aag gcg ttc tcg gcg gcg gcg gac ggg acc ggc 6960 Ala Asp Gly HisCys Lys Ala Phe Ser Ala Ala Ala Asp Gly Thr Gly 2305 2310 2315 2320 tggggt gag ggt gtg ggg atg ctg ctg gtg gag cgg ctc tcc gac gcc 7008 Trp GlyGlu Gly Val Gly Met Leu Leu Val Glu Arg Leu Ser Asp Ala 2325 2330 2335cat cgc aac ggt cac cgt gtc ctg gcc gtg gtg cgt ggc agt gcg gtc 7056 HisArg Asn Gly His Arg Val Leu Ala Val Val Arg Gly Ser Ala Val 2340 23452350 aac cag gac ggt gcg agc aac ggt ctg acc gcg ccc aac ggg ccg tcc7104 Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro Ser2355 2360 2365 cag cag cgt gtc atc cgc cag gcc ctc gcc aac gcc ggc ttgtcg gcc 7152 Gln Gln Arg Val Ile Arg Gln Ala Leu Ala Asn Ala Gly Leu SerAla 2370 2375 2380 ggt gat gtc gac gcg gtg gag gcc cac ggc acc ggc accact ttg ggc 7200 Gly Asp Val Asp Ala Val Glu Ala His Gly Thr Gly Thr ThrLeu Gly 2385 2390 2395 2400 gac ccg atc gag gcc cag gcc ctc ctc gcg acctac gga cag gac cgt 7248 Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr TyrGly Gln Asp Arg 2405 2410 2415 gcc ggc gag ggg ccg ctg tgg ctg ggc tcggtc aag tcc aat gtc ggt 7296 Ala Gly Glu Gly Pro Leu Trp Leu Gly Ser ValLys Ser Asn Val Gly 2420 2425 2430 cac aca cag gct gcc gcg ggc gtc gccggg gtg atc aag atg gtg atg 7344 His Thr Gln Ala Ala Ala Gly Val Ala GlyVal Ile Lys Met Val Met 2435 2440 2445 gcg ctg cgg cat ggt ctg ctg ccgcgg acg ttg cat gtg gat gag ccg 7392 Ala Leu Arg His Gly Leu Leu Pro ArgThr Leu His Val Asp Glu Pro 2450 2455 2460 tcg ccg cat gtg gac tgg tccgcg ggt gcg gtg cag ctg ctg acg gag 7440 Ser Pro His Val Asp Trp Ser AlaGly Ala Val Gln Leu Leu Thr Glu 2465 2470 2475 2480 acg gtg ccc tgg cccggc ggg gag ggg cgg cta cgg cgg gca gga gtg 7488 Thr Val Pro Trp Pro GlyGly Glu Gly Arg Leu Arg Arg Ala Gly Val 2485 2490 2495 tca tca ttc ggcgtc agc ggc acc aac gcc cac gtc atc ctc gaa gaa 7536 Ser Ser Phe Gly ValSer Gly Thr Asn Ala His Val Ile Leu Glu Glu 2500 2505 2510 gca ccc gccgac gac gtt ccg ggg gga cca ccc gcc ggc gag ggt gac 7584 Ala Pro Ala AspAsp Val Pro Gly Gly Pro Pro Ala Gly Glu Gly Asp 2515 2520 2525 gcg ggcagc gac gat gag gct gct gcc ggc agt cct ggg gtg tgg ccg 7632 Ala Gly SerAsp Asp Glu Ala Ala Ala Gly Ser Pro Gly Val Trp Pro 2530 2535 2540 tggctg gtg tcg gcc aag tcg cag ccg gcc ctg cgc gcc cag gcc cag 7680 Trp LeuVal Ser Ala Lys Ser Gln Pro Ala Leu Arg Ala Gln Ala Gln 2545 2550 25552560 gcc ctg cac gcc cac ctc acc gac cac ccc ggc ctc gac ctc gcg gat7728 Ala Leu His Ala His Leu Thr Asp His Pro Gly Leu Asp Leu Ala Asp2565 2570 2575 gtc gga tac acc ctc gcc cac gcc cgc gcc gtg ttc gac caccgc gcc 7776 Val Gly Tyr Thr Leu Ala His Ala Arg Ala Val Phe Asp His ArgAla 2580 2585 2590 acc ctc atc gcc gcg gac cgc gac acg ttc ctg caa gcactc cag gca 7824 Thr Leu Ile Ala Ala Asp Arg Asp Thr Phe Leu Gln Ala LeuGln Ala 2595 2600 2605 ctc gcc gca ggc gag ccc cac ccc gcc gtc atc cacagc agc gcc ccg 7872 Leu Ala Ala Gly Glu Pro His Pro Ala Val Ile His SerSer Ala Pro 2610 2615 2620 ggc ggg acc ggg acc ggg gag gcc gca gga aagacc gca ttc atc tgc 7920 Gly Gly Thr Gly Thr Gly Glu Ala Ala Gly Lys ThrAla Phe Ile Cys 2625 2630 2635 2640 tcc gga cag ggc acc caa cgc ccc ggcatg gcc cac ggc ctc tac cac 7968 Ser Gly Gln Gly Thr Gln Arg Pro Gly MetAla His Gly Leu Tyr His 2645 2650 2655 acc cac ccc gtc ttc gcc gcc gcactc aac gac atc tgc acc cac ctc 8016 Thr His Pro Val Phe Ala Ala Ala LeuAsn Asp Ile Cys Thr His Leu 2660 2665 2670 gac ccc cac ctc gac cac cccctc ctc ccc ctc ctc acc caa aac gac 8064 Asp Pro His Leu Asp His Pro LeuLeu Pro Leu Leu Thr Gln Asn Asp 2675 2680 2685 aac gac aac gag gac gcggcc gca ctg ctc cag cag acc cgc tac gcc 8112 Asn Asp Asn Glu Asp Ala AlaAla Leu Leu Gln Gln Thr Arg Tyr Ala 2690 2695 2700 cag ccc gcc ctc ttcgcc ttc cag gtc gcc ctc cac cgc ctc ctc acc 8160 Gln Pro Ala Leu Phe AlaPhe Gln Val Ala Leu His Arg Leu Leu Thr 2705 2710 2715 2720 gac ggc taccac atc acc ccc cac tac tac gcc gga cac tcc ctc ggc 8208 Asp Gly Tyr HisIle Thr Pro His Tyr Tyr Ala Gly His Ser Leu Gly 2725 2730 2735 gaa atcacc gcc gcc cac ctc gcc ggc atc ctc acc ctc acc gac gcc 8256 Glu Ile ThrAla Ala His Leu Ala Gly Ile Leu Thr Leu Thr Asp Ala 2740 2745 2750 accacc ctc atc acc caa cgc gcc acc ctc atg caa acc atg ccc ccc 8304 Thr ThrLeu Ile Thr Gln Arg Ala Thr Leu Met Gln Thr Met Pro Pro 2755 2760 2765ggc acc atg acc acc ctc cac acc acc ccc cac cac atc acc cac cac 8352 GlyThr Met Thr Thr Leu His Thr Thr Pro His His Ile Thr His His 2770 27752780 ctc acc gcc cac gaa aac gac ctc gcc atc gcc gcc atc aac acc ccc8400 Leu Thr Ala His Glu Asn Asp Leu Ala Ile Ala Ala Ile Asn Thr Pro2785 2790 2795 2800 acc tcc ctc gtc atc agc ggc acc ccc cac acc gtc caacac atc acc 8448 Thr Ser Leu Val Ile Ser Gly Thr Pro His Thr Val Gln HisIle Thr 2805 2810 2815 acc ctc tgc caa caa caa ggc atc aaa acc aaa accctc ccc acc aac 8496 Thr Leu Cys Gln Gln Gln Gly Ile Lys Thr Lys Thr LeuPro Thr Asn 2820 2825 2830 cac gcc ttc cac tcc ccc cac acc aac ccc atcctc aac caa ctc cac 8544 His Ala Phe His Ser Pro His Thr Asn Pro Ile LeuAsn Gln Leu His 2835 2840 2845 cag cac acc caa acc ctc acc tac cac ccaccc cac acc ccc ctc atc 8592 Gln His Thr Gln Thr Leu Thr Tyr His Pro ProHis Thr Pro Leu Ile 2850 2855 2860 acc gcc aac acc cca ccc gac caa ctcctc acc ccc cac tac tgg acc 8640 Thr Ala Asn Thr Pro Pro Asp Gln Leu LeuThr Pro His Tyr Trp Thr 2865 2870 2875 2880 caa caa gcc cgc aac acc gtcgac tac gcc acc acc acc caa acc ctc 8688 Gln Gln Ala Arg Asn Thr Val AspTyr Ala Thr Thr Thr Gln Thr Leu 2885 2890 2895 cac caa cac ggc gtc accacc tac atc gaa ctc gga ccc gac aac acc 8736 His Gln His Gly Val Thr ThrTyr Ile Glu Leu Gly Pro Asp Asn Thr 2900 2905 2910 ctc acc acc ctc acccac cac aac ctc ccc aac ccc ccc acc acc acc 8784 Leu Thr Thr Leu Thr HisHis Asn Leu Pro Asn Pro Pro Thr Thr Thr 2915 2920 2925 ctc acc ctc acccac ccc cac cac cac ccc caa acc cac ctc ctc acc 8832 Leu Thr Leu Thr HisPro His His His Pro Gln Thr His Leu Leu Thr 2930 2935 2940 aac ctc gccaaa acc acc acc acc tgg cac ccc cac cac tac acc cac 8880 Asn Leu Ala LysThr Thr Thr Thr Trp His Pro His His Tyr Thr His 2945 2950 2955 2960 cacgac aac caa ccc cac acc cac acc cac ctc gac ctc ccc acc tac 8928 His AspAsn Gln Pro His Thr His Thr His Leu Asp Leu Pro Thr Tyr 2965 2970 2975ccc ttc caa cac cac cac tac tgg ctc gaa agc aca cag ccc ggt gcc 8976 ProPhe Gln His His His Tyr Trp Leu Glu Ser Thr Gln Pro Gly Ala 2980 29852990 ggc aac gtg tca gca gcc gga ctc gac ccc acc gaa cac ccc cta ctc9024 Gly Asn Val Ser Ala Ala Gly Leu Asp Pro Thr Glu His Pro Leu Leu2995 3000 3005 ggc gcc aca ttg gaa ctg gcg act gac ggt gga gcg ctt cttgca ggg 9072 Gly Ala Thr Leu Glu Leu Ala Thr Asp Gly Gly Ala Leu Leu AlaGly 3010 3015 3020 cgc ttg tct ttg agg tcg cat ccg tgg ctg gct gac catgcc gtc ggc 9120 Arg Leu Ser Leu Arg Ser His Pro Trp Leu Ala Asp His AlaVal Gly 3025 3030 3035 3040 ggc acg gtg ctg ctg tcg ggc gcc acc ttc ctcgaa ctc gcc ctt cat 9168 Gly Thr Val Leu Leu Ser Gly Ala Thr Phe Leu GluLeu Ala Leu His 3045 3050 3055 gcg ggc aca tac gtg ggc tgc gac cga gtggat gag ctg acg ctg cat 9216 Ala Gly Thr Tyr Val Gly Cys Asp Arg Val AspGlu Leu Thr Leu His 3060 3065 3070 gcg ccg ctg gtg gtt cct gtg gat gggggt gtg agt gtg cag gtt ggg 9264 Ala Pro Leu Val Val Pro Val Asp Gly GlyVal Ser Val Gln Val Gly 3075 3080 3085 gtt gcg gct gcg gat ggg gag gggcgg cgt ttg gtg agt gtg tat gcg 9312 Val Ala Ala Ala Asp Gly Glu Gly ArgArg Leu Val Ser Val Tyr Ala 3090 3095 3100 cgg ggt ggg agt gct tgt ggtggg ggt ggt gcg tcg ggt ggg gtg tgg 9360 Arg Gly Gly Ser Ala Cys Gly GlyGly Gly Ala Ser Gly Gly Val Trp 3105 3110 3115 3120 acg tgt cat gcc tcgggg gtg ctg gtt gag gct gct gct ggt ggt gtg 9408 Thr Cys His Ala Ser GlyVal Leu Val Glu Ala Ala Ala Gly Gly Val 3125 3130 3135 gtg gtg gat ggtctg gcg ggg gtg tgg ccg ccg cgg ggt gcg gtg gcg 9456 Val Val Asp Gly LeuAla Gly Val Trp Pro Pro Arg Gly Ala Val Ala 3140 3145 3150 gtg gat gtcgat ggt gtc cgt gac cgt ttg gct ggg gct ggt tgt gtt 9504 Val Asp Val AspGly Val Arg Asp Arg Leu Ala Gly Ala Gly Cys Val 3155 3160 3165 ttg gggccg gtg ttt tcg ggg ctg cgt gcg gtg tgg cgt gat ggg ggg 9552 Leu Gly ProVal Phe Ser Gly Leu Arg Ala Val Trp Arg Asp Gly Gly 3170 3175 3180 gatttg ctg gct gag gtg tgt ctg ccg gag gag gcg tgg ggt gat gcg 9600 Asp LeuLeu Ala Glu Val Cys Leu Pro Glu Glu Ala Trp Gly Asp Ala 3185 3190 31953200 gct ggt ttt ggg ctg cat ccg gcg ttg ctg gat ggt gtg gtc cag ccg9648 Ala Gly Phe Gly Leu His Pro Ala Leu Leu Asp Gly Val Val Gln Pro3205 3210 3215 ttg tcg gtg ttg ctt ccg ggt ggg acg ggg ttt ggg gag ggggcg ggg 9696 Leu Ser Val Leu Leu Pro Gly Gly Thr Gly Phe Gly Glu Gly AlaGly 3220 3225 3230 ttc ggg gag ggt gtt cgg gtg ccg gct gtg tgg ggt ggtgtg tcg ctt 9744 Phe Gly Glu Gly Val Arg Val Pro Ala Val Trp Gly Gly ValSer Leu 3235 3240 3245 cac cgg gcg ggt gtg acc ggt gtg cgg gtg cgt gtgtcg gct gtc ggg 9792 His Arg Ala Gly Val Thr Gly Val Arg Val Arg Val SerAla Val Gly 3250 3255 3260 cgg ggc ggc ggg cgt gag gcg gtg tcg gtc gtggtc ggg gat gag gcg 9840 Arg Gly Gly Gly Arg Glu Ala Val Ser Val Val ValGly Asp Glu Ala 3265 3270 3275 3280 ggt gtg ccg gtg gcg tcg gtc gat cgtctt gag ttg cgg cct gtg gat 9888 Gly Val Pro Val Ala Ser Val Asp Arg LeuGlu Leu Arg Pro Val Asp 3285 3290 3295 atg ggt cag ttg cgt gct gtc tcggtt tcg gcg ggg cgg cgg ggt tcg 9936 Met Gly Gln Leu Arg Ala Val Ser ValSer Ala Gly Arg Arg Gly Ser 3300 3305 3310 ctg tat gcg gtg cag tgg gctgag gtg ggt cct gtg ccg gtg tgt ggg 9984 Leu Tyr Ala Val Gln Trp Ala GluVal Gly Pro Val Pro Val Cys Gly 3315 3320 3325 cag gcg tgg gcg tgg cacgag gac gtg ggt gag agc ggt ggt ggg cct 10032 Gln Ala Trp Ala Trp HisGlu Asp Val Gly Glu Ser Gly Gly Gly Pro 3330 3335 3340 gtg ccg ggg gtggtg gtg ttg cgg tgc ccg gat gcc ggt gcc ggt ggc 10080 Val Pro Gly ValVal Val Leu Arg Cys Pro Asp Ala Gly Ala Gly Gly 3345 3350 3355 3360 ggtggc ggt ggc ggt ggt ggc ggt ggt gtg ggt gag gtt gtt ggt ggg 10128 GlyGly Gly Gly Gly Gly Gly Gly Gly Val Gly Glu Val Val Gly Gly 3365 33703375 gtg ttg ggt gtg gtg cag ggg tgg ctg ggg ctg gag cgg ttt gcg ggt10176 Val Leu Gly Val Val Gln Gly Trp Leu Gly Leu Glu Arg Phe Ala Gly3380 3385 3390 tcg cgg ctg gtg gtg gtg acc cgg ggt gcg gtg gtg gcc ggcccg gag 10224 Ser Arg Leu Val Val Val Thr Arg Gly Ala Val Val Ala GlyPro Glu 3395 3400 3405 gac ggc ccg gtg gat gtg gtg ggt gcg tcg gtg tggggg ctg gtg cgt 10272 Asp Gly Pro Val Asp Val Val Gly Ala Ser Val TrpGly Leu Val Arg 3410 3415 3420 tcg gcg cag gct gag cat ccg gac cgg tttgtc ctc ctc gac ctc gac 10320 Ser Ala Gln Ala Glu His Pro Asp Arg PheVal Leu Leu Asp Leu Asp 3425 3430 3435 3440 acc gac acc ggc acc gac ctcgac acc ggt gct ggt gct ggt tgg ggc 10368 Thr Asp Thr Gly Thr Asp LeuAsp Thr Gly Ala Gly Ala Gly Trp Gly 3445 3450 3455 gtg gat ggt ggg cgtgtg gcg gcg gtg gtg gcg tgt ggt gag ccg cag 10416 Val Asp Gly Gly ArgVal Ala Ala Val Val Ala Cys Gly Glu Pro Gln 3460 3465 3470 ttg gcg gtgcgt ggg gag cgg ttg ctg gcc gca cgc ctg aaa cga ctt 10464 Leu Ala ValArg Gly Glu Arg Leu Leu Ala Ala Arg Leu Lys Arg Leu 3475 3480 3485 gagtca tcc ggt gat gtt cca gcc cag cgg tcc ggt gac aca cga gcc 10512 GluSer Ser Gly Asp Val Pro Ala Gln Arg Ser Gly Asp Thr Arg Ala 3490 34953500 cgg cgg tcc gac gtg cct gcc cag cgc tcc ggt ggc gtg cct gct cgg10560 Arg Arg Ser Asp Val Pro Ala Gln Arg Ser Gly Gly Val Pro Ala Arg3505 3510 3515 3520 cgg tcg gtt gat gta tcg ggt cgg gag gtg ttg ccg tggttg tcg ggt 10608 Arg Ser Val Asp Val Ser Gly Arg Glu Val Leu Pro TrpLeu Ser Gly 3525 3530 3535 ggg tcg gtg ttg gtg acg ggt ggg acg ggt gtgctg ggt gcg gcg gtg 10656 Gly Ser Val Leu Val Thr Gly Gly Thr Gly ValLeu Gly Ala Ala Val 3540 3545 3550 gcg cgg cat ctg gct ggt gtg tgt ggggtg cgg gat ctg ctg ttg gtg 10704 Ala Arg His Leu Ala Gly Val Cys GlyVal Arg Asp Leu Leu Leu Val 3555 3560 3565 agc cgg cgt ggt ccg gat gctccg ggt gcg gag ggt ctg cgg gcg gag 10752 Ser Arg Arg Gly Pro Asp AlaPro Gly Ala Glu Gly Leu Arg Ala Glu 3570 3575 3580 ctg gcc gcg ttg ggggcg gag gtg cgg att gtt gcg tgt gat gtg ggg 10800 Leu Ala Ala Leu GlyAla Glu Val Arg Ile Val Ala Cys Asp Val Gly 3585 3590 3595 3600 gag cggcgg gag gtg gtc cgg ctg ctg gag ggt gtt cct gcc ggg tgt 10848 Glu ArgArg Glu Val Val Arg Leu Leu Glu Gly Val Pro Ala Gly Cys 3605 3610 3615ccg ctg acg ggt gtc gtg cat gcg gct ggt gtg ctg gac gat gcg acg 10896Pro Leu Thr Gly Val Val His Ala Ala Gly Val Leu Asp Asp Ala Thr 36203625 3630 atc gcc tct ctc acg ccc gag cgg ctg ggc acg gtg ttc gcg gccaag 10944 Ile Ala Ser Leu Thr Pro Glu Arg Leu Gly Thr Val Phe Ala AlaLys 3635 3640 3645 gtg gat gcc gct ctt ttg ctg gat gag ctg acg cgg ggtatg gag ctg 10992 Val Asp Ala Ala Leu Leu Leu Asp Glu Leu Thr Arg GlyMet Glu Leu 3650 3655 3660 tcg gcg ttc gtg ctg ttc tcc tcg gcc gcg gggatc ctg ggg tcg gcc 11040 Ser Ala Phe Val Leu Phe Ser Ser Ala Ala GlyIle Leu Gly Ser Ala 3665 3670 3675 3680 ggg cag ggc aac tac gcc gcg gccaat gcc gct ctg gac gcg ctg gcg 11088 Gly Gln Gly Asn Tyr Ala Ala AlaAsn Ala Ala Leu Asp Ala Leu Ala 3685 3690 3695 tac cgg cgg cgg gcg gcgggt ctg ccg ggg gtg tcg ctg gcg tgg ggg 11136 Tyr Arg Arg Arg Ala AlaGly Leu Pro Gly Val Ser Leu Ala Trp Gly 3700 3705 3710 ctg tgg gaa gaggcc agc ggg atg acc ggg cac ctg gcc ggc acc gac 11184 Leu Trp Glu GluAla Ser Gly Met Thr Gly His Leu Ala Gly Thr Asp 3715 3720 3725 cac cggcgc atc atc cgt tcc ggt ctg cat ccc atg tcg acc ccg gac 11232 His ArgArg Ile Ile Arg Ser Gly Leu His Pro Met Ser Thr Pro Asp 3730 3735 3740gca ctg gcc ctc ttc gat gcg gcc ctg gct ctg gac cgg ccg gtc ctg 11280Ala Leu Ala Leu Phe Asp Ala Ala Leu Ala Leu Asp Arg Pro Val Leu 37453750 3755 3760 ctg ccc gcc gac ctg cgt ccc gcc ccg ccc ctg ccg ccc ctgctg cag 11328 Leu Pro Ala Asp Leu Arg Pro Ala Pro Pro Leu Pro Pro LeuLeu Gln 3765 3770 3775 gac ctc ctg ccc gcc acc cgc cgc cgc acc acc cgcacc acc act acc 11376 Asp Leu Leu Pro Ala Thr Arg Arg Arg Thr Thr ArgThr Thr Thr Thr 3780 3785 3790 ggt ggt gcg gac aac ggc gcc cag ctg cacgcc cgg ctg gcc ggc cag 11424 Gly Gly Ala Asp Asn Gly Ala Gln Leu HisAla Arg Leu Ala Gly Gln 3795 3800 3805 aca cac gaa caa cag cac acc accctc ctc gcc ctg gtc cgc tcc cac 11472 Thr His Glu Gln Gln His Thr ThrLeu Leu Ala Leu Val Arg Ser His 3810 3815 3820 atc gcc acc gtc ctg ggccac acc acc ccc gac acc atc ccc ccc gac 11520 Ile Ala Thr Val Leu GlyHis Thr Thr Pro Asp Thr Ile Pro Pro Asp 3825 3830 3835 3840 cgc gcg ttccgc gac ctc ggc ttc gac tcc ctc acc gcc gtc gaa cta 11568 Arg Ala PheArg Asp Leu Gly Phe Asp Ser Leu Thr Ala Val Glu Leu 3845 3850 3855 cgcaac cgg ctc tcc cgc acc acc gga ctc cgc ctc ccc acc acc ctc 11616 ArgAsn Arg Leu Ser Arg Thr Thr Gly Leu Arg Leu Pro Thr Thr Leu 3860 38653870 gcc ttc gac cac ccc aac ccc acc acc ctc acc cac cac ctc cac aca11664 Ala Phe Asp His Pro Asn Pro Thr Thr Leu Thr His His Leu His Thr3875 3880 3885 caa ctc cag cca caa ccg gac aac gct gtc gcc ccc gtg ttggcg gag 11712 Gln Leu Gln Pro Gln Pro Asp Asn Ala Val Ala Pro Val LeuAla Glu 3890 3895 3900 ctc gac aaa ctc gaa tcc gcc ctc tcc gcc ctc gacaaa acc gac agc 11760 Leu Asp Lys Leu Glu Ser Ala Leu Ser Ala Leu AspLys Thr Asp Ser 3905 3910 3915 3920 gcc agc gaa aga gtc acc ctg cgg ctgaag tca ctc atg ttg agg tgg 11808 Ala Ser Glu Arg Val Thr Leu Arg LeuLys Ser Leu Met Leu Arg Trp 3925 3930 3935 aac gca ccc cag cat ccg acagcc gaa agc gct gat gac gac gag aag 11856 Asn Ala Pro Gln His Pro ThrAla Glu Ser Ala Asp Asp Asp Glu Lys 3940 3945 3950 ttc aca tcg gca acagag gct gag att ttc aaa ttc att gac aac gac 11904 Phe Thr Ser Ala ThrGlu Ala Glu Ile Phe Lys Phe Ile Asp Asn Asp 3955 3960 3965 ctc ggc ctgtcc tgaaccggac gcctgccact ccgcccgtat ccgctgggcc 11956 Leu Gly Leu Ser3970 ctgctaggac gtga atg caa ttg gcg aat gaa gcg aag ctc ctg gaa tac12006 Met Gln Leu Ala Asn Glu Ala Lys Leu Leu Glu Tyr 3975 3980 ctc aagcgc gtc act gcg gac ctg gac cgc act cgc cgt cgc ctg tac 12054 Leu LysArg Val Thr Ala Asp Leu Asp Arg Thr Arg Arg Arg Leu Tyr 3985 3990 39954000 gag gtg gtc gag cgt gag cag gag ccg atc gcg att gtg ggg atg gcg12102 Glu Val Val Glu Arg Glu Gln Glu Pro Ile Ala Ile Val Gly Met Ala4005 4010 4015 tgt cgt tac cca ggc ggg gcg acg tca ccc acg cga ctg tggcat ctc 12150 Cys Arg Tyr Pro Gly Gly Ala Thr Ser Pro Thr Arg Leu TrpHis Leu 4020 4025 4030 gtc aag tcc cag acg gac gct atc ggg gag ttc ccgacc gac cgt gga 12198 Val Lys Ser Gln Thr Asp Ala Ile Gly Glu Phe ProThr Asp Arg Gly 4035 4040 4045 tgg aac ctg gag cag ctc tac gac ccg gacccc gac cgc tca gga acc 12246 Trp Asn Leu Glu Gln Leu Tyr Asp Pro AspPro Asp Arg Ser Gly Thr 4050 4055 4060 agt tac acg cgc agc gga ggg tttctc tat gac gcg ggc gac ttc gac 12294 Ser Tyr Thr Arg Ser Gly Gly PheLeu Tyr Asp Ala Gly Asp Phe Asp 4065 4070 4075 4080 gcc gcg ttc ttc gagttg tca ccg cgt gag gcg ctg gca atg gac ccg 12342 Ala Ala Phe Phe GluLeu Ser Pro Arg Glu Ala Leu Ala Met Asp Pro 4085 4090 4095 cag cag cgcctg ctg ctc gaa acc act tgg gaa acg ttc gaa cag ggc 12390 Gln Gln ArgLeu Leu Leu Glu Thr Thr Trp Glu Thr Phe Glu Gln Gly 4100 4105 4110 ggaatc gac ccg agg tcc atg cgc gga agc cgg acc ggg gtt ttc gtg 12438 GlyIle Asp Pro Arg Ser Met Arg Gly Ser Arg Thr Gly Val Phe Val 4115 41204125 ggg atc aat ccg gag gac tac acc acc gga tac aca cat cag ccc tca12486 Gly Ile Asn Pro Glu Asp Tyr Thr Thr Gly Tyr Thr His Gln Pro Ser4130 4135 4140 aac gca gtc gag ggc tac ctg ctc act ggc agc gcg gca agcatt gcg 12534 Asn Ala Val Glu Gly Tyr Leu Leu Thr Gly Ser Ala Ala SerIle Ala 4145 4150 4155 4160 tca ggc cgt atc tcc tac aac ttc ggg ctc gaaggc cct gcg atc act 12582 Ser Gly Arg Ile Ser Tyr Asn Phe Gly Leu GluGly Pro Ala Ile Thr 4165 4170 4175 atc gac acc gcg tgt tcc tcc tcg ctcgtc gcc ctg cat ctg gcc tgc 12630 Ile Asp Thr Ala Cys Ser Ser Ser LeuVal Ala Leu His Leu Ala Cys 4180 4185 4190 caa gcg ctc cgg tcc ggt gaatgc acc atg gcg ctc gca ggc ggc gcc 12678 Gln Ala Leu Arg Ser Gly GluCys Thr Met Ala Leu Ala Gly Gly Ala 4195 4200 4205 tcc gtc atg gcc actccc ttc gtc ttc acc gag ttc tct cgc cag cgg 12726 Ser Val Met Ala ThrPro Phe Val Phe Thr Glu Phe Ser Arg Gln Arg 4210 4215 4220 ggc ctg gccgca gac ggc cgg tgc aag gcg ttt tcg gcg gcg gcg gac 12774 Gly Leu AlaAla Asp Gly Arg Cys Lys Ala Phe Ser Ala Ala Ala Asp 4225 4230 4235 4240ggg acc ggc tgg tcc gag ggt gtg ggg atg ctg ctg gtg gag cgg ctc 12822Gly Thr Gly Trp Ser Glu Gly Val Gly Met Leu Leu Val Glu Arg Leu 42454250 4255 tcc gac gcc cgc cgc aac ggt cac cgt gtc ctg gcc gtc gtc cgcggc 12870 Ser Asp Ala Arg Arg Asn Gly His Arg Val Leu Ala Val Val ArgGly 4260 4265 4270 agc gcc gtc aac cag gac ggc gca agc aac ggc ctg accgca ccc aac 12918 Ser Ala Val Asn Gln Asp Gly Ala Ser Asn Gly Leu ThrAla Pro Asn 4275 4280 4285 ggt cgt tca caa gtc aag gtc atc cgc cag gctttg gcc aac gca cac 12966 Gly Arg Ser Gln Val Lys Val Ile Arg Gln AlaLeu Ala Asn Ala His 4290 4295 4300 ctc tcc cct gcc gat gtc gat gcg gtggag gcc cac ggc acg ggg acc 13014 Leu Ser Pro Ala Asp Val Asp Ala ValGlu Ala His Gly Thr Gly Thr 4305 4310 4315 4320 acc ctg ggc gac ccg atcgag gct caa gcc ctc gtc gaa gcc tac ggt 13062 Thr Leu Gly Asp Pro IleGlu Ala Gln Ala Leu Val Glu Ala Tyr Gly 4325 4330 4335 cag gac cgc cccaac ggc cgc ccc ctc tgg ctc gga acc ctc aag tcc 13110 Gln Asp Arg ProAsn Gly Arg Pro Leu Trp Leu Gly Thr Leu Lys Ser 4340 4345 4350 aac atcggg cac tcc atg gcc gct gcg ggt gtg ggc ggg gtc atc aag 13158 Asn IleGly His Ser Met Ala Ala Ala Gly Val Gly Gly Val Ile Lys 4355 4360 4365atg gtg atg gcg ctg cgg aat ggt ctg ctg ccg cgg acg ttg cat gtg 13206Met Val Met Ala Leu Arg Asn Gly Leu Leu Pro Arg Thr Leu His Val 43704375 4380 gat gag ccg tcg ccg cat gtg gac tgg tcc gcg ggt gcg gtg cagctg 13254 Asp Glu Pro Ser Pro His Val Asp Trp Ser Ala Gly Ala Val GlnLeu 4385 4390 4395 4400 ctg acg gag acg gtg ccc tgg ccc ggc ggg gag gggcgg cta cgg cgg 13302 Leu Thr Glu Thr Val Pro Trp Pro Gly Gly Glu GlyArg Leu Arg Arg 4405 4410 4415 gca gga gtg tca tca ttc ggc gtc agc ggcacc aac gcc cac gtc atc 13350 Ala Gly Val Ser Ser Phe Gly Val Ser GlyThr Asn Ala His Val Ile 4420 4425 4430 ctc gag gaa gca ccc gcc cac aacatc ccg tca gac aca ccc gcc gac 13398 Leu Glu Glu Ala Pro Ala His AsnIle Pro Ser Asp Thr Pro Ala Asp 4435 4440 4445 gac gtc ccg gga gaa tcagcc gcc gac gag gat gcc ggt agt ggc gat 13446 Asp Val Pro Gly Glu SerAla Ala Asp Glu Asp Ala Gly Ser Gly Asp 4450 4455 4460 gag gct gct gccggc agt cca ggg gtg tgg ccg tgg ctg gtg tcg gcc 13494 Glu Ala Ala AlaGly Ser Pro Gly Val Trp Pro Trp Leu Val Ser Ala 4465 4470 4475 4480 aagtcg cag ccg gcc ctg cgc gcc cag gcc cag gcc ctg cac gcc cac 13542 LysSer Gln Pro Ala Leu Arg Ala Gln Ala Gln Ala Leu His Ala His 4485 44904495 ctc acc gac cac ccc ggc ctc gac ctc gcc gac gtc ggg tac acc ctc13590 Leu Thr Asp His Pro Gly Leu Asp Leu Ala Asp Val Gly Tyr Thr Leu4500 4505 4510 gcc cac gcc cgc gcc gtg ttc gac cac cgc gcc acc ctc atcgcc gcc 13638 Ala His Ala Arg Ala Val Phe Asp His Arg Ala Thr Leu IleAla Ala 4515 4520 4525 gac cgc gac acc ttc ctg caa gca ctc cag gca ctcgcc gca ggc gaa 13686 Asp Arg Asp Thr Phe Leu Gln Ala Leu Gln Ala LeuAla Ala Gly Glu 4530 4535 4540 ccc cac ccc gcc gtc atc cac agc agc gcccca ggc ggg acc ggg acc 13734 Pro His Pro Ala Val Ile His Ser Ser AlaPro Gly Gly Thr Gly Thr 4545 4550 4555 4560 ggg gag gcc gca gga aag accgca ttc atc tgc tcc gga cag ggc acc 13782 Gly Glu Ala Ala Gly Lys ThrAla Phe Ile Cys Ser Gly Gln Gly Thr 4565 4570 4575 caa cgc ccc ggc atggcc cac ggc ctc tac cac acc cac ccc gtc ttc 13830 Gln Arg Pro Gly MetAla His Gly Leu Tyr His Thr His Pro Val Phe 4580 4585 4590 gcc gcc gcactc aac gac atc tgc acc cac ctc gac ccc cac ctc gac 13878 Ala Ala AlaLeu Asn Asp Ile Cys Thr His Leu Asp Pro His Leu Asp 4595 4600 4605 cacccc ctc ctc ccc ctc ctc acc cag gac ccc aac acc cag gac acc 13926 HisPro Leu Leu Pro Leu Leu Thr Gln Asp Pro Asn Thr Gln Asp Thr 4610 46154620 acc acc ctc gaa gaa gcg gcc gca ctg ctc cag cag acc cgc tac gcc13974 Thr Thr Leu Glu Glu Ala Ala Ala Leu Leu Gln Gln Thr Arg Tyr Ala4625 4630 4635 4640 cag ccc gcc ctc ttc gcc ttc cag gtc gcc ctc cac cgcctc ctc acc 14022 Gln Pro Ala Leu Phe Ala Phe Gln Val Ala Leu His ArgLeu Leu Thr 4645 4650 4655 gac ggc tac cac atc acc ccc cac tac tac gccgga cac tcc ctc ggc 14070 Asp Gly Tyr His Ile Thr Pro His Tyr Tyr AlaGly His Ser Leu Gly 4660 4665 4670 gaa atc acc gcc gcc cac ctc gcc ggcatc ctc acc ctc acc gac gcc 14118 Glu Ile Thr Ala Ala His Leu Ala GlyIle Leu Thr Leu Thr Asp Ala 4675 4680 4685 acc acc ctc atc acc caa cgcgcc acc ctc atg caa acc atg ccc ccc 14166 Thr Thr Leu Ile Thr Gln ArgAla Thr Leu Met Gln Thr Met Pro Pro 4690 4695 4700 ggc acc atg acc accctc cac acc acc ccc cac cac atc acc cac cac 14214 Gly Thr Met Thr ThrLeu His Thr Thr Pro His His Ile Thr His His 4705 4710 4715 4720 ctc accgcc cac gaa aac gac ctc gcc atc gcc gcc atc aac acc ccc 14262 Leu ThrAla His Glu Asn Asp Leu Ala Ile Ala Ala Ile Asn Thr Pro 4725 4730 4735acc tcc ctc gtc atc agc ggc acc ccc cac acc gtc caa cac atc acc 14310Thr Ser Leu Val Ile Ser Gly Thr Pro His Thr Val Gln His Ile Thr 47404745 4750 acc ctc tgc caa caa caa ggc atc aaa acc aaa acc ctc ccc accaac 14358 Thr Leu Cys Gln Gln Gln Gly Ile Lys Thr Lys Thr Leu Pro ThrAsn 4755 4760 4765 cac gcc ttc cac tcc ccc cac acc aac ccc atc ctc aaccaa ctc cac 14406 His Ala Phe His Ser Pro His Thr Asn Pro Ile Leu AsnGln Leu His 4770 4775 4780 cag cac acc caa acc ctc acc tac cac cca ccccac acc ccc ctc atc 14454 Gln His Thr Gln Thr Leu Thr Tyr His Pro ProHis Thr Pro Leu Ile 4785 4790 4795 4800 acc gcc aac acc cca ccc gac caactc ctc acc ccc cac tac tgg acc 14502 Thr Ala Asn Thr Pro Pro Asp GlnLeu Leu Thr Pro His Tyr Trp Thr 4805 4810 4815 caa caa gcc cgc aac accgtc gac tac gcc acc acc acc caa acc ctc 14550 Gln Gln Ala Arg Asn ThrVal Asp Tyr Ala Thr Thr Thr Gln Thr Leu 4820 4825 4830 cac caa cac ggcgtc acc acc tac atc gaa ctc gga ccc gac aac acc 14598 His Gln His GlyVal Thr Thr Tyr Ile Glu Leu Gly Pro Asp Asn Thr 4835 4840 4845 ctc accacc ctc acc cac gac aac ctc ccc aac acc ccc acc acc acc 14646 Leu ThrThr Leu Thr His Asp Asn Leu Pro Asn Thr Pro Thr Thr Thr 4850 4855 4860ctc acc ctc acc cac ccc cac cac cac ccc caa acc cac ctc ctc acc 14694Leu Thr Leu Thr His Pro His His His Pro Gln Thr His Leu Leu Thr 48654870 4875 4880 aac ctc gcc aaa acc acc acc acc tgg cac ccc cac cac tacacc cac 14742 Asn Leu Ala Lys Thr Thr Thr Thr Trp His Pro His His TyrThr His 4885 4890 4895 cac cac aac caa ccc cac acc cac acc cac ctc gacctc ccc acc tac 14790 His His Asn Gln Pro His Thr His Thr His Leu AspLeu Pro Thr Tyr 4900 4905 4910 ccc ttc caa cac cac cac tac tgg ctc caacca ccc ggc aag ccg agc 14838 Pro Phe Gln His His His Tyr Trp Leu GlnPro Pro Gly Lys Pro Ser 4915 4920 4925 gac ccg tca ccg agc gaa ggc cgtgag caa gcc acg acc cca tca acc 14886 Asp Pro Ser Pro Ser Glu Gly ArgGlu Gln Ala Thr Thr Pro Ser Thr 4930 4935 4940 ccg ctg cgt gat gtc ctcgtg ggc aag tct ccg cag gag cga gac gaa 14934 Pro Leu Arg Asp Val LeuVal Gly Lys Ser Pro Gln Glu Arg Asp Glu 4945 4950 4955 4960 gag ctg ttgcgc ctg gtg cgc acc cat gcg gcc gct gtg ctg ggc cat 14982 Glu Leu LeuArg Leu Val Arg Thr His Ala Ala Ala Val Leu Gly His 4965 4970 4975 gccact ccc gaa gtg atc gtt ccg aac aag gcc ttc aaa gag ctg ggt 15030 AlaThr Pro Glu Val Ile Val Pro Asn Lys Ala Phe Lys Glu Leu Gly 4980 49854990 ttt gat tct ctc gcc gca att cag ctt cgt aat cga ctg ctt gct gac15078 Phe Asp Ser Leu Ala Ala Ile Gln Leu Arg Asn Arg Leu Leu Ala Asp4995 5000 5005 gtt gac ctg ccg ctt ccg gcc acg ctg atc ttc gat tac cccact ccg 15126 Val Asp Leu Pro Leu Pro Ala Thr Leu Ile Phe Asp Tyr ProThr Pro 5010 5015 5020 atg gcg ctt tgc cag ttc ctc cgg gcg gcg atc gtcgga gcg gac aca 15174 Met Ala Leu Cys Gln Phe Leu Arg Ala Ala Ile ValGly Ala Asp Thr 5025 5030 5035 5040 ggc acg acc act cgt ctg ccg cta actgcg gtc ccc gcc gac gag ccg 15222 Gly Thr Thr Thr Arg Leu Pro Leu ThrAla Val Pro Ala Asp Glu Pro 5045 5050 5055 atc gcc atc gtc ggc atg gcctgt cgg tac ccc ggt gat gta cgg acg 15270 Ile Ala Ile Val Gly Met AlaCys Arg Tyr Pro Gly Asp Val Arg Thr 5060 5065 5070 gtc gat gat ctc tggcag gtg gtc agt ggt ggc cat gac gcg atc ggc 15318 Val Asp Asp Leu TrpGln Val Val Ser Gly Gly His Asp Ala Ile Gly 5075 5080 5085 gga ttc ccgacg aac cgt ggg tgg gac ctc gac acg ctg tac aac ccg 15366 Gly Phe ProThr Asn Arg Gly Trp Asp Leu Asp Thr Leu Tyr Asn Pro 5090 5095 5100 gacccg gac cac cac gga acc agc tac acc cgg agc ggc gga ttc ctt 15414 AspPro Asp His His Gly Thr Ser Tyr Thr Arg Ser Gly Gly Phe Leu 5105 51105115 5120 tac gac gca ggc aat ttc gat ccc gac ttc ttc ggt atc agt ccgcgt 15462 Tyr Asp Ala Gly Asn Phe Asp Pro Asp Phe Phe Gly Ile Ser ProArg 5125 5130 5135 gag gca ctg gcg atg gac ccg cag cag cgg ctg ctg ctggaa aca gcg 15510 Glu Ala Leu Ala Met Asp Pro Gln Gln Arg Leu Leu LeuGlu Thr Ala 5140 5145 5150 tgg gag agc atc gaa cac gcc tgc atc aac cccgac agc ctc cgt ggc 15558 Trp Glu Ser Ile Glu His Ala Cys Ile Asn ProAsp Ser Leu Arg Gly 5155 5160 5165 aca cca acc ggc gtc ttc gcc ggg ctgacc tac cac gac tac gcc gcg 15606 Thr Pro Thr Gly Val Phe Ala Gly LeuThr Tyr His Asp Tyr Ala Ala 5170 5175 5180 cgc ttt ccc aca gct ccg gcaggg ttc gag ggg tat ctc ggg cac gga 15654 Arg Phe Pro Thr Ala Pro AlaGly Phe Glu Gly Tyr Leu Gly His Gly 5185 5190 5195 5200 agc gca ggc agtatc gcc tcg ggt cgt gtc gcc tac gct ctc ggc ctg 15702 Ser Ala Gly SerIle Ala Ser Gly Arg Val Ala Tyr Ala Leu Gly Leu 5205 5210 5215 gaa ggtccg gcc ctc aca gtc gac act gcc tgc tct tcg tcc ctg gtc 15750 Glu GlyPro Ala Leu Thr Val Asp Thr Ala Cys Ser Ser Ser Leu Val 5220 5225 5230gct ctg cac ctg gcc tgt cag gcg ctg cgg tcc ggc gag tgt tcc atg 15798Ala Leu His Leu Ala Cys Gln Ala Leu Arg Ser Gly Glu Cys Ser Met 52355240 5245 gcc ctc gcg ggt ggc gtc acg gtg atg tca acc ccg gcc ggg ttcgtg 15846 Ala Leu Ala Gly Gly Val Thr Val Met Ser Thr Pro Ala Gly PheVal 5250 5255 5260 gag ttt tcg cgg cag cgg ggc ctg gcc gtg gac ggg cggtgc aag gcg 15894 Glu Phe Ser Arg Gln Arg Gly Leu Ala Val Asp Gly ArgCys Lys Ala 5265 5270 5275 5280 ttc tcg gca gcg gct gac ggc acc ggc tggggt gag ggt gtc gga atg 15942 Phe Ser Ala Ala Ala Asp Gly Thr Gly TrpGly Glu Gly Val Gly Met 5285 5290 5295 ctg ctg gtg gag cgg ctg tcg gacgcg cgg cgg ctc ggt cac cga atc 15990 Leu Leu Val Glu Arg Leu Ser AspAla Arg Arg Leu Gly His Arg Ile 5300 5305 5310 ctc gcg gtg gtg cgt ggcagt gcg gtc aat cag gac ggt gcg agc aac 16038 Leu Ala Val Val Arg GlySer Ala Val Asn Gln Asp Gly Ala Ser Asn 5315 5320 5325 ggg ctg acg gcgccc aac ggg ccg tcc cag gag cgt gtc atc cgc ctg 16086 Gly Leu Thr AlaPro Asn Gly Pro Ser Gln Glu Arg Val Ile Arg Leu 5330 5335 5340 gcc ctggcc aac gcg gac ctg acc ccc gcc gac gtc gat gcg gtg gag 16134 Ala LeuAla Asn Ala Asp Leu Thr Pro Ala Asp Val Asp Ala Val Glu 5345 5350 53555360 gcc cac ggc acc ggc acc act ttg ggc gac ccg atc gag gcc cag gcc16182 Ala His Gly Thr Gly Thr Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala5365 5370 5375 ctc ctc gcc acc tac gga cag gac cgc ccc ggc aac gaa ccgctg tgg 16230 Leu Leu Ala Thr Tyr Gly Gln Asp Arg Pro Gly Asn Glu ProLeu Trp 5380 5385 5390 ctg ggc tcg atg aag tcg aac atc ggc cac gcg caggct gcc gca ggt 16278 Leu Gly Ser Met Lys Ser Asn Ile Gly His Ala GlnAla Ala Ala Gly 5395 5400 5405 gtg ggc ggg gtc atc aag atg gtg atg gcgctg cgg aat ggt ctg ctg 16326 Val Gly Gly Val Ile Lys Met Val Met AlaLeu Arg Asn Gly Leu Leu 5410 5415 5420 ccg cgg acg ttg cat gtg gat gagccg tcg ccg cat gtg gac tgg tcc 16374 Pro Arg Thr Leu His Val Asp GluPro Ser Pro His Val Asp Trp Ser 5425 5430 5435 5440 gcg ggg gcg gtg cagctg ctg acg gag acg gtg ccc tgg ccc ggc ggg 16422 Ala Gly Ala Val GlnLeu Leu Thr Glu Thr Val Pro Trp Pro Gly Gly 5445 5450 5455 gag ggg cggctg cgg cgg gca gga gtg tca tcg ttc ggc gtc agc ggc 16470 Glu Gly ArgLeu Arg Arg Ala Gly Val Ser Ser Phe Gly Val Ser Gly 5460 5465 5470 accaac gcc cac gtc atc ctc gaa gaa gca ccc gcc cac aac atc ccg 16518 ThrAsn Ala His Val Ile Leu Glu Glu Ala Pro Ala His Asn Ile Pro 5475 54805485 tca gac aca ccc gcc gac gac gcc ccg gga gaa gca gcc gcc gac gat16566 Ser Asp Thr Pro Ala Asp Asp Ala Pro Gly Glu Ala Ala Ala Asp Asp5490 5495 5500 gtt ccg ggg gaa gcg gcc ggc gac gac gcc ggt acc ggc ggggaa gcg 16614 Val Pro Gly Glu Ala Ala Gly Asp Asp Ala Gly Thr Gly GlyGlu Ala 5505 5510 5515 5520 act ggt cct gct gcc ggc agt cca ggg gtg tggccg tgg ctg gtg tcg 16662 Thr Gly Pro Ala Ala Gly Ser Pro Gly Val TrpPro Trp Leu Val Ser 5525 5530 5535 gcc aag tcg cag ccg gcc ctg cgc gcccag gcc cag gcc ctg cac gcc 16710 Ala Lys Ser Gln Pro Ala Leu Arg AlaGln Ala Gln Ala Leu His Ala 5540 5545 5550 cac ctc acc gac cac ccc ggcctc gac ctc gcc gac gtc ggg tac acc 16758 His Leu Thr Asp His Pro GlyLeu Asp Leu Ala Asp Val Gly Tyr Thr 5555 5560 5565 ctc gcc cac gcc cgcgcc gtg ttc gac cac cgc gcc acc ctc atc gcc 16806 Leu Ala His Ala ArgAla Val Phe Asp His Arg Ala Thr Leu Ile Ala 5570 5575 5580 gcc gac cgcgac acc ttc ctg caa gca ctc cag gca ctc gcc gca ggc 16854 Ala Asp ArgAsp Thr Phe Leu Gln Ala Leu Gln Ala Leu Ala Ala Gly 5585 5590 5595 5600gaa ccc cac ccc gcc gtc atc cac agc agc gcc cca ggc ggg acc ggg 16902Glu Pro His Pro Ala Val Ile His Ser Ser Ala Pro Gly Gly Thr Gly 56055610 5615 acc ggg gag gcc gca gga aag acc gca ttc atc tgc tcc gga cagggc 16950 Thr Gly Glu Ala Ala Gly Lys Thr Ala Phe Ile Cys Ser Gly GlnGly 5620 5625 5630 acc caa cgc ccc ggc atg gcc cac ggc ctc tac cac acccac ccc gtc 16998 Thr Gln Arg Pro Gly Met Ala His Gly Leu Tyr His ThrHis Pro Val 5635 5640 5645 ttc gcc gcc gca ctc aac gac atc tgc acc cacctc gac ccc cac ctc 17046 Phe Ala Ala Ala Leu Asn Asp Ile Cys Thr HisLeu Asp Pro His Leu 5650 5655 5660 gac cac ccc ctc ctc ccc ctc ctc acccag gac ccc aac acc cag gac 17094 Asp His Pro Leu Leu Pro Leu Leu ThrGln Asp Pro Asn Thr Gln Asp 5665 5670 5675 5680 acc acc acc ctc gaa gaagcg gcc gca ctg ctc cag cag acc ccg tac 17142 Thr Thr Thr Leu Glu GluAla Ala Ala Leu Leu Gln Gln Thr Pro Tyr 5685 5690 5695 gcc cag ccc gccctc ttc gcc ttc cag gtc gcc ctc cac cgc ctc ctc 17190 Ala Gln Pro AlaLeu Phe Ala Phe Gln Val Ala Leu His Arg Leu Leu 5700 5705 5710 acc gacggc tac cac atc acc ccc cac tac tac gcc gga cac tcc ctc 17238 Thr AspGly Tyr His Ile Thr Pro His Tyr Tyr Ala Gly His Ser Leu 5715 5720 5725ggc gaa atc acc gcc gcc cac ctc gcc ggc atc ctc acc ctc acc gac 17286Gly Glu Ile Thr Ala Ala His Leu Ala Gly Ile Leu Thr Leu Thr Asp 57305735 5740 gcc acc acc ctc atc acc caa cgc gcc acc ctc atg caa acc atgccc 17334 Ala Thr Thr Leu Ile Thr Gln Arg Ala Thr Leu Met Gln Thr MetPro 5745 5750 5755 5760 ccc ggc acc atg acc acc ctc cac acc acc ccc caccac atc acc cac 17382 Pro Gly Thr Met Thr Thr Leu His Thr Thr Pro HisHis Ile Thr His 5765 5770 5775 cac ctc acc gcc cac gaa aac gac ctc gccatc gcc gcc atc aac acc 17430 His Leu Thr Ala His Glu Asn Asp Leu AlaIle Ala Ala Ile Asn Thr 5780 5785 5790 ccc acc tcc ctc gtc atc agc ggcacc ccc cac acc gtc caa cac atc 17478 Pro Thr Ser Leu Val Ile Ser GlyThr Pro His Thr Val Gln His Ile 5795 5800 5805 acc acc ctc tgc caa caacaa ggc atc aaa acc aaa acc ctc ccc acc 17526 Thr Thr Leu Cys Gln GlnGln Gly Ile Lys Thr Lys Thr Leu Pro Thr 5810 5815 5820 aaa aac gcc ttccac tcc ccc cac acc aac ccc atc ctc aac caa ctc 17574 Lys Asn Ala PheHis Ser Pro His Thr Asn Pro Ile Leu Asn Gln Leu 5825 5830 5835 5840 caccag cac acc caa acc ctc acc tac cac cca ccc cac acc ccc ctc 17622 HisGln His Thr Gln Thr Leu Thr Tyr His Pro Pro His Thr Pro Leu 5845 58505855 atc acc gcc aac acc cca ccc gac caa ctc ctc acc ccc cac tac tgg17670 Ile Thr Ala Asn Thr Pro Pro Asp Gln Leu Leu Thr Pro His Tyr Trp5860 5865 5870 acc caa caa gcc cgc aac acc gtc gac tac gcc acc acc acccaa acc 17718 Thr Gln Gln Ala Arg Asn Thr Val Asp Tyr Ala Thr Thr ThrGln Thr 5875 5880 5885 ctc cac caa cac ggc gtc acc acc tac atc gaa ctcgga ccc gac aac 17766 Leu His Gln His Gly Val Thr Thr Tyr Ile Glu LeuGly Pro Asp Asn 5890 5895 5900 acc ctc acc acc ctc acc cac cac aac ctcccc aac acc ccc acc acc 17814 Thr Leu Thr Thr Leu Thr His His Asn LeuPro Asn Thr Pro Thr Thr 5905 5910 5915 5920 acc ctc acc ctc acc cac ccccac cac cac ccc caa acc cac ctc ctc 17862 Thr Leu Thr Leu Thr His ProHis His His Pro Gln Thr His Leu Leu 5925 5930 5935 acc aac ctc gcc aaaacc acc acc acc tgg cac ccc cac cac tac acc 17910 Thr Asn Leu Ala LysThr Thr Thr Thr Trp His Pro His His Tyr Thr 5940 5945 5950 cac cac cacaac caa ccc cac acc cac acc cac ctc gac ctc ccc acc 17958 His His HisAsn Gln Pro His Thr His Thr His Leu Asp Leu Pro Thr 5955 5960 5965 tacccc ttc caa cac cag cac tac tgg ctc gaa agc aca cag ccg ggt 18006 TyrPro Phe Gln His Gln His Tyr Trp Leu Glu Ser Thr Gln Pro Gly 5970 59755980 gcc gga tcc ggt tcg ggt tcc ggt tcc ggg cgg gca ggg act gcg ggc18054 Ala Gly Ser Gly Ser Gly Ser Gly Ser Gly Arg Ala Gly Thr Ala Gly5985 5990 5995 6000 ggg acg gca gag gtg gag tcg cgg ttc tgg gac gcg gtggcc cgc cag 18102 Gly Thr Ala Glu Val Glu Ser Arg Phe Trp Asp Ala ValAla Arg Gln 6005 6010 6015 gac ctg gaa acg gtc gcg acc acg ctc gcc gtgccc ccc tcc gcc ggc 18150 Asp Leu Glu Thr Val Ala Thr Thr Leu Ala ValPro Pro Ser Ala Gly 6020 6025 6030 ctg gac acg gtg gtg ccc gca ctc tccgcc tgg cac cgc cac caa cac 18198 Leu Asp Thr Val Val Pro Ala Leu SerAla Trp His Arg His Gln His 6035 6040 6045 gac caa gcc cgc atc aac acctgg acc tac cag gaa acc tgg aaa ccc 18246 Asp Gln Ala Arg Ile Asn ThrTrp Thr Tyr Gln Glu Thr Trp Lys Pro 6050 6055 6060 ctc acc ctc ccc accacc cac caa ccc cac caa acc tgg ctc atc gcc 18294 Leu Thr Leu Pro ThrThr His Gln Pro His Gln Thr Trp Leu Ile Ala 6065 6070 6075 6080 atc cccgaa acc cag acc cac cac ccc cac atc acc aac atc ctc acc 18342 Ile ProGlu Thr Gln Thr His His Pro His Ile Thr Asn Ile Leu Thr 6085 6090 6095aac ctc cac cac cac ggc atc acc ccc atc ccc ctc acc ctc aac cac 18390Asn Leu His His His Gly Ile Thr Pro Ile Pro Leu Thr Leu Asn His 61006105 6110 acc cac acc aac ccc caa cac ctc cac cac acc cga caa caa gcccaa 18438 Thr His Thr Asn Pro Gln His Leu His His Thr Arg Gln Gln AlaGln 6115 6120 6125 aac cac acc acc gga ccc atc acc ggc ctg ctc tcc ctcctc gcc ctc 18486 Asn His Thr Thr Gly Pro Ile Thr Gly Leu Leu Ser LeuLeu Ala Leu 6130 6135 6140 gac gaa aca ccc cac ccc cac cac ccc cac acaccc acc ggc acc ctc 18534 Asp Glu Thr Pro His Pro His His Pro His ThrPro Thr Gly Thr Leu 6145 6150 6155 6160 ctc aac ctc acc ctc acc caa acccac acc caa acc cac cca cca acc 18582 Leu Asn Leu Thr Leu Thr Gln ThrHis Thr Gln Thr His Pro Pro Thr 6165 6170 6175 ccc ctc tgg tac gcc accacc aac gcc acc acc acc cac ccc aac gac 18630 Pro Leu Trp Tyr Ala ThrThr Asn Ala Thr Thr Thr His Pro Asn Asp 6180 6185 6190 ccc ctc aca cacccc acc caa gcc caa acc tgg gga ctc gcc cgc acc 18678 Pro Leu Thr HisPro Thr Gln Ala Gln Thr Trp Gly Leu Ala Arg Thr 6195 6200 6205 acc ctcctc gaa cac ccc acc cac acc gcc gga atc atc gac ctc ccc 18726 Thr LeuLeu Glu His Pro Thr His Thr Ala Gly Ile Ile Asp Leu Pro 6210 6215 6220acc acc ccc acc ccc cac acc ctc cac cac ctc acc caa acc ctc acc 18774Thr Thr Pro Thr Pro His Thr Leu His His Leu Thr Gln Thr Leu Thr 62256230 6235 6240 caa ccc cac cac caa acc caa ctc gcc atc cgc acc acc ggcacc cac 18822 Gln Pro His His Gln Thr Gln Leu Ala Ile Arg Thr Thr GlyThr His 6245 6250 6255 acc cgc cgc ctc acc ccc acc acc ctc acc ccc acacac caa cca ccc 18870 Thr Arg Arg Leu Thr Pro Thr Thr Leu Thr Pro ThrHis Gln Pro Pro 6260 6265 6270 acc ccc acc ccc cac gga acc acc ctc atcacc ggc gga acc ggc gcc 18918 Thr Pro Thr Pro His Gly Thr Thr Leu IleThr Gly Gly Thr Gly Ala 6275 6280 6285 ctc gcc acc cac ctc acc cac cacctc acc acc cac caa ccc acc caa 18966 Leu Ala Thr His Leu Thr His HisLeu Thr Thr His Gln Pro Thr Gln 6290 6295 6300 cac ctc ctc ctc acc agccga acc ggc ccc cac acc ccc cac gca caa 19014 His Leu Leu Leu Thr SerArg Thr Gly Pro His Thr Pro His Ala Gln 6305 6310 6315 6320 cac ctc accacc caa ctc caa caa aaa ggc atc cac ctc acc atc acc 19062 His Leu ThrThr Gln Leu Gln Gln Lys Gly Ile His Leu Thr Ile Thr 6325 6330 6335 acctgc gac acc agc aac cca gac caa ctc caa caa ctc ctc aac acc 19110 ThrCys Asp Thr Ser Asn Pro Asp Gln Leu Gln Gln Leu Leu Asn Thr 6340 63456350 atc ccc cca caa cac ccc ctc acc acc gtc atc cac acc gca ggc atc19158 Ile Pro Pro Gln His Pro Leu Thr Thr Val Ile His Thr Ala Gly Ile6355 6360 6365 ctc gac gac gcc acc ctc acc aac ctc acc ccc acc caa ctcaac aac 19206 Leu Asp Asp Ala Thr Leu Thr Asn Leu Thr Pro Thr Gln LeuAsn Asn 6370 6375 6380 gtc ctc cgc gcc aaa gcc cac agc gcc cac ctc ctccac caa ctc acc 19254 Val Leu Arg Ala Lys Ala His Ser Ala His Leu LeuHis Gln Leu Thr 6385 6390 6395 6400 caa cac acc ccc ctc aac gcc ttc gtcctc tac tcc tcc gcc gcc gcc 19302 Gln His Thr Pro Leu Asn Ala Phe ValLeu Tyr Ser Ser Ala Ala Ala 6405 6410 6415 acc ttc ggc gca ccc ggc caagcc aac tac gcc gca gcc aac gcc tac 19350 Thr Phe Gly Ala Pro Gly GlnAla Asn Tyr Ala Ala Ala Asn Ala Tyr 6420 6425 6430 ctc gac gcc ctc gcccac cac cgc cac acc cac cac ctc ccc gcc acc 19398 Leu Asp Ala Leu AlaHis His Arg His Thr His His Leu Pro Ala Thr 6435 6440 6445 agc atc gcctgg ggc acc tgg caa gga aac gga ctg gcg act ggt caa 19446 Ser Ile AlaTrp Gly Thr Trp Gln Gly Asn Gly Leu Ala Thr Gly Gln 6450 6455 6460 gtcagc gaa cat ctc cgc cgc cgc ggg atg ttc gcc atg ccg ccc gag 19494 ValSer Glu His Leu Arg Arg Arg Gly Met Phe Ala Met Pro Pro Glu 6465 64706475 6480 ttg gcg gtc aca gct gtt gac ggc gcg atc gcg agc ggg cgc ccgagt 19542 Leu Ala Val Thr Ala Val Asp Gly Ala Ile Ala Ser Gly Arg ProSer 6485 6490 6495 ctc ctc gtc gcc gat atc gac tgg aag aaa ttg gga ccggtt ctc tcc 19590 Leu Leu Val Ala Asp Ile Asp Trp Lys Lys Leu Gly ProVal Leu Ser 6500 6505 6510 agc aag tcg tcg gtc ttg ctc gag gac ctt ccccag gca cag gga act 19638 Ser Lys Ser Ser Val Leu Leu Glu Asp Leu ProGln Ala Gln Gly Thr 6515 6520 6525 gag gag gcg cgc agt acc gtt gag cagacg gag agc aca aac ctc cgg 19686 Glu Glu Ala Arg Ser Thr Val Glu GlnThr Glu Ser Thr Asn Leu Arg 6530 6535 6540 caa ctc ctc atg ggt cgg tcacgt tcc gag cag gaa gaa gag ctg ctc 19734 Gln Leu Leu Met Gly Arg SerArg Ser Glu Gln Glu Glu Glu Leu Leu 6545 6550 6555 6560 agc ctc gtc cgcatc cac tcc gcg gca gtg ctc ggg cgc gac gac tcc 19782 Ser Leu Val ArgIle His Ser Ala Ala Val Leu Gly Arg Asp Asp Ser 6565 6570 6575 gag gccatc ccg ccc ggt cgg ctg ttc agg gat cta ggg ttc gac tcg 19830 Glu AlaIle Pro Pro Gly Arg Leu Phe Arg Asp Leu Gly Phe Asp Ser 6580 6585 6590ctt gcg gcg gtg gag ctt cgc aac cac ctc gca gca cag acg gag ctg 19878Leu Ala Ala Val Glu Leu Arg Asn His Leu Ala Ala Gln Thr Glu Leu 65956600 6605 gct ctg ccg acg act ctc gtc ttc gat tac ccc agc ccc acc aagctc 19926 Ala Leu Pro Thr Thr Leu Val Phe Asp Tyr Pro Ser Pro Thr LysLeu 6610 6615 6620 gcc caa ttt ctg ctc tcc gag atc gcg gag ttc cag cccgac aac tca 19974 Ala Gln Phe Leu Leu Ser Glu Ile Ala Glu Phe Gln ProAsp Asn Ser 6625 6630 6635 6640 act ccg ctt ccg cga ccc cgg gca gag ctcgat gag ccg atc gcc atc 20022 Thr Pro Leu Pro Arg Pro Arg Ala Glu LeuAsp Glu Pro Ile Ala Ile 6645 6650 6655 gtt ggc atg gcc tgt cgc ttc cccggc gga gtg acc tcg gcg gac gac 20070 Val Gly Met Ala Cys Arg Phe ProGly Gly Val Thr Ser Ala Asp Asp 6660 6665 6670 ttc tgg gat ctg atc tcctcc gag cag gac gcg atc ggc gga ttc ccc 20118 Phe Trp Asp Leu Ile SerSer Glu Gln Asp Ala Ile Gly Gly Phe Pro 6675 6680 6685 acc gac cgc ggctgg gac ctg gac acg ctc tac gac ccc gac ccc gac 20166 Thr Asp Arg GlyTrp Asp Leu Asp Thr Leu Tyr Asp Pro Asp Pro Asp 6690 6695 6700 cac cccggc acc tgc tac acc cga aac ggc gga ttc ctc tac gac gca 20214 His ProGly Thr Cys Tyr Thr Arg Asn Gly Gly Phe Leu Tyr Asp Ala 6705 6710 67156720 ggc cac ttc gac gcc gaa ttc ttc ggc atc agc ccc cgc gaa gcc ctc20262 Gly His Phe Asp Ala Glu Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu6725 6730 6735 gcc atg gac ccc cag caa cga ctc ctc ctc gaa acc gcc tgggaa acc 20310 Ala Met Asp Pro Gln Gln Arg Leu Leu Leu Glu Thr Ala TrpGlu Thr 6740 6745 6750 atc gaa cac gcc ggc atc aac ccc cac acc ctc cacggc acc ccc acc 20358 Ile Glu His Ala Gly Ile Asn Pro His Thr Leu HisGly Thr Pro Thr 6755 6760 6765 gga gtc ttc acc ggc acc aac gga cag gaccac gcg gca cac atc cgt 20406 Gly Val Phe Thr Gly Thr Asn Gly Gln AspHis Ala Ala His Ile Arg 6770 6775 6780 cag gcc ccg agc ggt acc gag ggattc gtc ctg acc ggg gca gcc acc 20454 Gln Ala Pro Ser Gly Thr Glu GlyPhe Val Leu Thr Gly Ala Ala Thr 6785 6790 6795 6800 agc atc gcc tcc ggccga atc tcc tac atc ctc ggg ttg gaa ggg cct 20502 Ser Ile Ala Ser GlyArg Ile Ser Tyr Ile Leu Gly Leu Glu Gly Pro 6805 6810 6815 gcg gtc accctc gac aca gcg tgt tcc tcc tcg ctc gtc gcc ctg cac 20550 Ala Val ThrLeu Asp Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His 6820 6825 6830 ctcgcc tgc cag tcc ctc agg tcc ggt gaa tgc acc atg gcc ttg gcc 20598 LeuAla Cys Gln Ser Leu Arg Ser Gly Glu Cys Thr Met Ala Leu Ala 6835 68406845 ggc ggg gcc acg gtc atg acc acc ccg atc acc ttc acc gaa ttc gcc20646 Gly Gly Ala Thr Val Met Thr Thr Pro Ile Thr Phe Thr Glu Phe Ala6850 6855 6860 cgc caa cgc gga ctc gcc ccc gac ggg cgt tgc aag gcg ttctcg gcg 20694 Arg Gln Arg Gly Leu Ala Pro Asp Gly Arg Cys Lys Ala PheSer Ala 6865 6870 6875 6880 gcg gct gac ggt acc ggc tgg ggt gag ggt gtgggg atg ctg ctg gtg 20742 Ala Ala Asp Gly Thr Gly Trp Gly Glu Gly ValGly Met Leu Leu Val 6885 6890 6895 gag cgg ctc tcc gac gcc cgc cgc aacggt cac cgt gtc ctg gcc gtg 20790 Glu Arg Leu Ser Asp Ala Arg Arg AsnGly His Arg Val Leu Ala Val 6900 6905 6910 gtg cgt ggc agt gcg gtc aaccag gac ggt gcg agc aac ggt ctg acc 20838 Val Arg Gly Ser Ala Val AsnGln Asp Gly Ala Ser Asn Gly Leu Thr 6915 6920 6925 gcg ccc aac ggg ccctcc cag cag cgc gtc atc cgc cag gcc ctc gcc 20886 Ala Pro Asn Gly ProSer Gln Gln Arg Val Ile Arg Gln Ala Leu Ala 6930 6935 6940 aac gcg gacctg acc ccc gcc gac gtc gat gcg gtg gag gcc cac ggc 20934 Asn Ala AspLeu Thr Pro Ala Asp Val Asp Ala Val Glu Ala His Gly 6945 6950 6955 6960acc ggc acc act ttg ggc gac ccg atc gag gcc cag gcc atc ctc gcg 20982Thr Gly Thr Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala Ile Leu Ala 69656970 6975 acc tac gga cag gac cgt ccc ggc aac ggg ccg ttg tgg ctg ggctcc 21030 Thr Tyr Gly Gln Asp Arg Pro Gly Asn Gly Pro Leu Trp Leu GlySer 6980 6985 6990 gtc aag tcc aac gtc gga cac aca cag gcc gcg gcg ggcgtg gcc gga 21078 Val Lys Ser Asn Val Gly His Thr Gln Ala Ala Ala GlyVal Ala Gly 6995 7000 7005 gtg atc aag atg gtg atg gcc ctc cgc cac cggaca ctc cca ccg act 21126 Val Ile Lys Met Val Met Ala Leu Arg His ArgThr Leu Pro Pro Thr 7010 7015 7020 ctc cac gcg gat gag ccg tcg ccg catgtg gac tgg tcc gcg ggt gcg 21174 Leu His Ala Asp Glu Pro Ser Pro HisVal Asp Trp Ser Ala Gly Ala 7025 7030 7035 7040 gtg cag ctg ctg acg gagacg gtg ccc tgg ccc ggc ggg gag ggg cgg 21222 Val Gln Leu Leu Thr GluThr Val Pro Trp Pro Gly Gly Glu Gly Arg 7045 7050 7055 ccg cgg cgg gcagga gtg tca tca ttc ggc gtc agc ggc acc aac gcc 21270 Pro Arg Arg AlaGly Val Ser Ser Phe Gly Val Ser Gly Thr Asn Ala 7060 7065 7070 cac gtcatc ctc gaa gaa gca ccc gcc gac gac gtt ccg ggg gga cca 21318 His ValIle Leu Glu Glu Ala Pro Ala Asp Asp Val Pro Gly Gly Pro 7075 7080 7085ccc gcc gac gag gat gcc ggt agt ggc gag gag gct gct gcc ggc agt 21366Pro Ala Asp Glu Asp Ala Gly Ser Gly Glu Glu Ala Ala Ala Gly Ser 70907095 7100 cct ggg gtg tgg ccg tgg ctg gtg tcg gcc aag tcg cag ccg gccctg 21414 Pro Gly Val Trp Pro Trp Leu Val Ser Ala Lys Ser Gln Pro AlaLeu 7105 7110 7115 7120 cgc gcc cag gcc cag gcc ctg cac gcc cac ctc accgac cac ccc ggc 21462 Arg Ala Gln Ala Gln Ala Leu His Ala His Leu ThrAsp His Pro Gly 7125 7130 7135 ctc gac ctc gcc gac gtc gga tac acc ctcgcc cac gcc cgc gcc gtg 21510 Leu Asp Leu Ala Asp Val Gly Tyr Thr LeuAla His Ala Arg Ala Val 7140 7145 7150 ttc gac cac cgc gcc acc ctc atcgcc gcc gac cgc gac acc ttc ctg 21558 Phe Asp His Arg Ala Thr Leu IleAla Ala Asp Arg Asp Thr Phe Leu 7155 7160 7165 caa gca ctc cag gca ctcgcc gca ggc gaa ccc cac ccc gcc gtc atc 21606 Gln Ala Leu Gln Ala LeuAla Ala Gly Glu Pro His Pro Ala Val Ile 7170 7175 7180 cac agc agc gcccca ggc ggg acc ggg acc ggg gag gcc gca gga aag 21654 His Ser Ser AlaPro Gly Gly Thr Gly Thr Gly Glu Ala Ala Gly Lys 7185 7190 7195 7200 accgca ttc atc tgc tcc gga cag ggc acc caa cgc ccc ggc atg gcc 21702 ThrAla Phe Ile Cys Ser Gly Gln Gly Thr Gln Arg Pro Gly Met Ala 7205 72107215 cac ggc ctc tac cac acc cac ccc gtc ttc gcc gcc gca ctc aac gac21750 His Gly Leu Tyr His Thr His Pro Val Phe Ala Ala Ala Leu Asn Asp7220 7225 7230 atc tgc acc cac ctc gac ccc cac ctc gac cac ccc ctc ctcccc ctc 21798 Ile Cys Thr His Leu Asp Pro His Leu Asp His Pro Leu LeuPro Leu 7235 7240 7245 ctc acc caa aac gac aac gac aac gac aac gag gacgcg gcc gca ctg 21846 Leu Thr Gln Asn Asp Asn Asp Asn Asp Asn Glu AspAla Ala Ala Leu 7250 7255 7260 ctc cag cag acc ccg tac gcc cag ccc gccctc ttc gcc ttc cag gtc 21894 Leu Gln Gln Thr Pro Tyr Ala Gln Pro AlaLeu Phe Ala Phe Gln Val 7265 7270 7275 7280 gcc ctc cac cgc ctc ctc accgac ggc tac cac atc acc ccc cac tac 21942 Ala Leu His Arg Leu Leu ThrAsp Gly Tyr His Ile Thr Pro His Tyr 7285 7290 7295 tac gcc gga cac tccctc ggc gaa atc acc gcc gcc cac ctc gcc ggc 21990 Tyr Ala Gly His SerLeu Gly Glu Ile Thr Ala Ala His Leu Ala Gly 7300 7305 7310 atc ctc accctc acc gac gcc acc acc ctc atc acc caa cgc gcc acc 22038 Ile Leu ThrLeu Thr Asp Ala Thr Thr Leu Ile Thr Gln Arg Ala Thr 7315 7320 7325 ctcatg caa acc atg ccc ccc ggc acc atg acc acc ctc cac acc acc 22086 LeuMet Gln Thr Met Pro Pro Gly Thr Met Thr Thr Leu His Thr Thr 7330 73357340 cca cac cac atc acc cac cac ctc acc gcc cac gaa aac gac ctc gcc22134 Pro His His Ile Thr His His Leu Thr Ala His Glu Asn Asp Leu Ala7345 7350 7355 7360 atc gcc gcc atc aac acc ccc acc tcc ctc gtc atc agcggc acc ccc 22182 Ile Ala Ala Ile Asn Thr Pro Thr Ser Leu Val Ile SerGly Thr Pro 7365 7370 7375 cac acc gtc caa cac atc acc acc ctc tgc caacaa caa ggc atc aaa 22230 His Thr Val Gln His Ile Thr Thr Leu Cys GlnGln Gln Gly Ile Lys 7380 7385 7390 acc aaa acc ctc ccc acc aac cac gccttc cac tcc ccc cac acc aac 22278 Thr Lys Thr Leu Pro Thr Asn His AlaPhe His Ser Pro His Thr Asn 7395 7400 7405 ccc atc ctc aac caa ctc caccag cac acc caa acc ctc acc tac cac 22326 Pro Ile Leu Asn Gln Leu HisGln His Thr Gln Thr Leu Thr Tyr His 7410 7415 7420 cca ccc cac acc cccctc atc acc gcc aac acc cca ccc gac caa ctc 22374 Pro Pro His Thr ProLeu Ile Thr Ala Asn Thr Pro Pro Asp Gln Leu 7425 7430 7435 7440 ctc accccc cac tac tgg acc caa caa gcc cgc aac acc gtc gac tac 22422 Leu ThrPro His Tyr Trp Thr Gln Gln Ala Arg Asn Thr Val Asp Tyr 7445 7450 7455gcc acc acc acc caa acc ctc cac caa cac ggc gtc acc acc tac atc 22470Ala Thr Thr Thr Gln Thr Leu His Gln His Gly Val Thr Thr Tyr Ile 74607465 7470 gaa ctc gga ccc gac aac acc ctc acc acc ctc acc cac cac aacctc 22518 Glu Leu Gly Pro Asp Asn Thr Leu Thr Thr Leu Thr His His AsnLeu 7475 7480 7485 ccc aac acc ccc acc acc acc ctc acc ctc acc cac ccccac cac cac 22566 Pro Asn Thr Pro Thr Thr Thr Leu Thr Leu Thr His ProHis His His 7490 7495 7500 ccc caa acc cac ctc ctc acc aac ctc gcc aaaacc acc acc acc tgg 22614 Pro Gln Thr His Leu Leu Thr Asn Leu Ala LysThr Thr Thr Thr Trp 7505 7510 7515 7520 cac ccc cac cac tac acc cac caccac aac caa ccc cac acc cac acc 22662 His Pro His His Tyr Thr His HisHis Asn Gln Pro His Thr His Thr 7525 7530 7535 cac ctc gac ctc ccc acctac ccc ttc caa cac cac cac tac tgg ctc 22710 His Leu Asp Leu Pro ThrTyr Pro Phe Gln His His His Tyr Trp Leu 7540 7545 7550 gaa cta ccc agcgcc caa acc agc ccc ggt caa agg cgt tct cgc cgc 22758 Glu Leu Pro SerAla Gln Thr Ser Pro Gly Gln Arg Arg Ser Arg Arg 7555 7560 7565 tcg gctcca gac acc gcc gag tcg gag ttc tgg gac gcg gtg aac gag 22806 Ser AlaPro Asp Thr Ala Glu Ser Glu Phe Trp Asp Ala Val Asn Glu 7570 7575 7580gaa gac ctc cag agc ctc gcc gaa acc ctc gac atc gac gcc tct gct 22854Glu Asp Leu Gln Ser Leu Ala Glu Thr Leu Asp Ile Asp Ala Ser Ala 75857590 7595 7600 ctg gac acg gtg gtg ccc gca ctc tcc gcc tgg cac cgc caccaa cac 22902 Leu Asp Thr Val Val Pro Ala Leu Ser Ala Trp His Arg HisGln His 7605 7610 7615 gac caa gcc cgc atc aac acc tgg acc tac cag gaaacc tgg aaa ccc 22950 Asp Gln Ala Arg Ile Asn Thr Trp Thr Tyr Gln GluThr Trp Lys Pro 7620 7625 7630 ctc acc ctc ccc acc acc cac caa ccc caccaa acc tgg ctc atc gcc 22998 Leu Thr Leu Pro Thr Thr His Gln Pro HisGln Thr Trp Leu Ile Ala 7635 7640 7645 atc ccc gaa acc cag acc cac cacccc cac atc acc aac atc ctc acc 23046 Ile Pro Glu Thr Gln Thr His HisPro His Ile Thr Asn Ile Leu Thr 7650 7655 7660 aac ctc cac cac cac ggcatc acc ccc atc ccc ctc act gtc aac cac 23094 Asn Leu His His His GlyIle Thr Pro Ile Pro Leu Thr Val Asn His 7665 7670 7675 7680 acc cac accaac ccc caa cac ctc cac cac acc ctc cac cac acc cga 23142 Thr His ThrAsn Pro Gln His Leu His His Thr Leu His His Thr Arg 7685 7690 7695 caacaa gcc caa aac cac acc acc gga ccc atc acc ggc ctg ctc tcc 23190 GlnGln Ala Gln Asn His Thr Thr Gly Pro Ile Thr Gly Leu Leu Ser 7700 77057710 ctc ctc gcc ctc gac gaa aca ccc cac ccc cac cac ccc cac aca ccc23238 Leu Leu Ala Leu Asp Glu Thr Pro His Pro His His Pro His Thr Pro7715 7720 7725 acc ggc acc ctc ctc aac ctc acc ctc ccc caa acc cac acccaa acc 23286 Thr Gly Thr Leu Leu Asn Leu Thr Leu Pro Gln Thr His ThrGln Thr 7730 7735 7740 cac cca cca acc ccc ctc tgg tac gcc acc acc aacgcc acc acc acc 23334 His Pro Pro Thr Pro Leu Trp Tyr Ala Thr Thr AsnAla Thr Thr Thr 7745 7750 7755 7760 cac ccc aac gac ccc ctc aca cac cccacc caa gcc caa acc tgg gga 23382 His Pro Asn Asp Pro Leu Thr His ProThr Gln Ala Gln Thr Trp Gly 7765 7770 7775 ctc gcc cgc acc acc ctc ctcgaa cac ccc acc cac acc gcc gga atc 23430 Leu Ala Arg Thr Thr Leu LeuGlu His Pro Thr His Thr Ala Gly Ile 7780 7785 7790 atc gac ctc ccc accacc ccc acc ccc cac acc ctc cac cac ctc acc 23478 Ile Asp Leu Pro ThrThr Pro Thr Pro His Thr Leu His His Leu Thr 7795 7800 7805 caa acc ctcacc caa ccc cac cac caa acc caa ctc gcc atc cgc acc 23526 Gln Thr LeuThr Gln Pro His His Gln Thr Gln Leu Ala Ile Arg Thr 7810 7815 7820 accggc acc cac acc cgc cgc ctc acc ccc acc acc ctc acc ccc aca 23574 ThrGly Thr His Thr Arg Arg Leu Thr Pro Thr Thr Leu Thr Pro Thr 7825 78307835 7840 cac caa cca ccc acc ccc acc ccc cac gga acc acc ctc atc accggc 23622 His Gln Pro Pro Thr Pro Thr Pro His Gly Thr Thr Leu Ile ThrGly 7845 7850 7855 gga acc ggc gcc ctc gcc acc cac ctc acc cac cac ctcacc acc cac 23670 Gly Thr Gly Ala Leu Ala Thr His Leu Thr His His LeuThr Thr His 7860 7865 7870 caa ccc acc caa cac ctc ctc ctc acc agc cgaacc ggc ccc cac acc 23718 Gln Pro Thr Gln His Leu Leu Leu Thr Ser ArgThr Gly Pro His Thr 7875 7880 7885 ccc cac gca caa cac ctc acc acc caactc caa caa aaa ggc atc cac 23766 Pro His Ala Gln His Leu Thr Thr GlnLeu Gln Gln Lys Gly Ile His 7890 7895 7900 ctc acc atc acc acc tgc gacacc agc aac cca gac caa ctc caa caa 23814 Leu Thr Ile Thr Thr Cys AspThr Ser Asn Pro Asp Gln Leu Gln Gln 7905 7910 7915 7920 ctc ctc aac accatc ccc cca caa cac ccc ctc acc acc gtc atc cac 23862 Leu Leu Asn ThrIle Pro Pro Gln His Pro Leu Thr Thr Val Ile His 7925 7930 7935 acc gcaggc gtc aat ctc ttc gcc ccc gtg tcg gaa acc gat gcc gaa 23910 Thr AlaGly Val Asn Leu Phe Ala Pro Val Ser Glu Thr Asp Ala Glu 7940 7945 7950tcc ttc tct tcc gtt acg gca gcg aag gca acg ggc gcg gcg att ctg 23958Ser Phe Ser Ser Val Thr Ala Ala Lys Ala Thr Gly Ala Ala Ile Leu 79557960 7965 cat gag ttg ctg ctg gac cat gaa acg ctt gaa cac ttc att ctcttc 24006 His Glu Leu Leu Leu Asp His Glu Thr Leu Glu His Phe Ile LeuPhe 7970 7975 7980 tcg tcg ggc gcc ggc gct tgg ggc agc ggg aat cag tgcgca tac tcg 24054 Ser Ser Gly Ala Gly Ala Trp Gly Ser Gly Asn Gln CysAla Tyr Ser 7985 7990 7995 8000 gcg gcc aac gca tac ctg gac gcg ctc gcgacg cat cgt cag aca cat 24102 Ala Ala Asn Ala Tyr Leu Asp Ala Leu AlaThr His Arg Gln Thr His 8005 8010 8015 gga ctt ccc ggg gca tcg atc gcctgg ggc ccc tgg gcc gga aag ggc 24150 Gly Leu Pro Gly Ala Ser Ile AlaTrp Gly Pro Trp Ala Gly Lys Gly 8020 8025 8030 atg tcg gcc ggt gat gcggct cat ggt tac ctg gaa aag cgc ggc att 24198 Met Ser Ala Gly Asp AlaAla His Gly Tyr Leu Glu Lys Arg Gly Ile 8035 8040 8045 ctg ccg atg gagcca cgc atg gcg ctc gcg gca ttc cat cgt gcg cgg 24246 Leu Pro Met GluPro Arg Met Ala Leu Ala Ala Phe His Arg Ala Arg 8050 8055 8060 gcg cagcgg ccg aat tcc aac ctg atc atc gcg gac atc gac tgg gag 24294 Ala GlnArg Pro Asn Ser Asn Leu Ile Ile Ala Asp Ile Asp Trp Glu 8065 8070 80758080 cgc ttc gtc ccc gcc ttc acc gct cga cgc cac agc ccg ctc atc gag24342 Arg Phe Val Pro Ala Phe Thr Ala Arg Arg His Ser Pro Leu Ile Glu8085 8090 8095 gac att ccg gag gtt cgg caa gcg gct cag gag ctg gaa gcagct gcg 24390 Asp Ile Pro Glu Val Arg Gln Ala Ala Gln Glu Leu Glu AlaAla Ala 8100 8105 8110 tcg acg gca aag acg acc aca gct cag ccg att gcgacg tct ctc cgt 24438 Ser Thr Ala Lys Thr Thr Thr Ala Gln Pro Ile AlaThr Ser Leu Arg 8115 8120 8125 gag cga ttg gcc cga ctg acg tcc tca aagcag aac cag gtg ctg ctc 24486 Glu Arg Leu Ala Arg Leu Thr Ser Ser LysGln Asn Gln Val Leu Leu 8130 8135 8140 ggc ctg att cgg aca ggc atc tgcacc gtt ctc ggc ctt cgt aat ccg 24534 Gly Leu Ile Arg Thr Gly Ile CysThr Val Leu Gly Leu Arg Asn Pro 8145 8150 8155 8160 gaa ggc atc gag gaccaa cga gcc ttc cgc gac ctc ggc ttc gac tcg 24582 Glu Gly Ile Glu AspGln Arg Ala Phe Arg Asp Leu Gly Phe Asp Ser 8165 8170 8175 ctg acg tcggct cag ttc agc aag gaa ctc gcc aag gaa acc gga ctg 24630 Leu Thr SerAla Gln Phe Ser Lys Glu Leu Ala Lys Glu Thr Gly Leu 8180 8185 8190 ccactc ccc ccg tcc ctg gtc ttc gac tat ccc acc ccg cag gaa tgt 24678 ProLeu Pro Pro Ser Leu Val Phe Asp Tyr Pro Thr Pro Gln Glu Cys 8195 82008205 gct gcc cat ctg cgc aca caa ctc gtc gac cta gac gac gaa gag gac24726 Ala Ala His Leu Arg Thr Gln Leu Val Asp Leu Asp Asp Glu Glu Asp8210 8215 8220 gcg gca ctg tcg aat gct ctc ccg caa gtg gcc cat cgg cgtacc gtc 24774 Ala Ala Leu Ser Asn Ala Leu Pro Gln Val Ala His Arg ArgThr Val 8225 8230 8235 8240 gag gac gaa ccg atc gcc atc atc ggt atg gcatgt cgc ttc ccc ggc 24822 Glu Asp Glu Pro Ile Ala Ile Ile Gly Met AlaCys Arg Phe Pro Gly 8245 8250 8255 ggc gta cgt tct gcc gac gac ctg tgggaa ttg ctc gct tcg ggt aag 24870 Gly Val Arg Ser Ala Asp Asp Leu TrpGlu Leu Leu Ala Ser Gly Lys 8260 8265 8270 gac gct atc ggc gtc ttc ccgacc gac cgc ggc tgg gac ctg gac acg 24918 Asp Ala Ile Gly Val Phe ProThr Asp Arg Gly Trp Asp Leu Asp Thr 8275 8280 8285 ctc tac gac ccc gacccc gac cac ccc ggc acc tgc tac acc cga aac 24966 Leu Tyr Asp Pro AspPro Asp His Pro Gly Thr Cys Tyr Thr Arg Asn 8290 8295 8300 ggc gga ttcctc tac ggc gca ggc cac ttc gac gcc gaa ttc ttc ggc 25014 Gly Gly PheLeu Tyr Gly Ala Gly His Phe Asp Ala Glu Phe Phe Gly 8305 8310 8315 8320atc agc ccc cgc gaa gcc ctc gcc atg gac ccc cag caa cga ctc ctc 25062Ile Ser Pro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln Arg Leu Leu 83258330 8335 ctc gaa acc gcc tgg gaa acc atc gaa cac gcc ggc atc aac ccccac 25110 Leu Glu Thr Ala Trp Glu Thr Ile Glu His Ala Gly Ile Asn ProHis 8340 8345 8350 acc ctc cac ggc acc ccc acc gga gtc ttc gcc gga atcaac gct caa 25158 Thr Leu His Gly Thr Pro Thr Gly Val Phe Ala Gly IleAsn Ala Gln 8355 8360 8365 gac cac gcc gcg cat atc cgc caa agc cgt gatgtg gag acc atc gag 25206 Asp His Ala Ala His Ile Arg Gln Ser Arg AspVal Glu Thr Ile Glu 8370 8375 8380 ggc tac gcc ctg acc ggc agt tcg ggaagt gtg gcg tcc ggc cgg gtg 25254 Gly Tyr Ala Leu Thr Gly Ser Ser GlySer Val Ala Ser Gly Arg Val 8385 8390 8395 8400 gcc tac acg ctc ggg ctcgaa ggc ccc gcg gtg tcg gtg gat acg gcg 25302 Ala Tyr Thr Leu Gly LeuGlu Gly Pro Ala Val Ser Val Asp Thr Ala 8405 8410 8415 tgt tcg tcg tcgttg gtg gcg ttg cat tgg gcg gcg cag gcg ttg cgt 25350 Cys Ser Ser SerLeu Val Ala Leu His Trp Ala Ala Gln Ala Leu Arg 8420 8425 8430 gcg ggtgag tgt tcg atg gcg ctt gcc ggg ggt gtg acg gtg atg tcg 25398 Ala GlyGlu Cys Ser Met Ala Leu Ala Gly Gly Val Thr Val Met Ser 8435 8440 8445tct ccg ggt acg ttt gtg gag ttc tca cgt cag cgg ggt ctg gcc gcg 25446Ser Pro Gly Thr Phe Val Glu Phe Ser Arg Gln Arg Gly Leu Ala Ala 84508455 8460 gac ggg cgg tgc aag gcc tat tcg gcg gct gct gac ggt acc ggctgg 25494 Asp Gly Arg Cys Lys Ala Tyr Ser Ala Ala Ala Asp Gly Thr GlyTrp 8465 8470 8475 8480 gcc gag ggt gtg ggg atg ctg ctg gtg gag cgg ctctcc gac gcc cgt 25542 Ala Glu Gly Val Gly Met Leu Leu Val Glu Arg LeuSer Asp Ala Arg 8485 8490 8495 cgc aac ggt cac cgt gtc ctg gcc gtg gtgcgt ggc agt gcg gtc aac 25590 Arg Asn Gly His Arg Val Leu Ala Val ValArg Gly Ser Ala Val Asn 8500 8505 8510 cag gac ggt gcg agc aac ggt ctgacc gcg ccc aac ggg ccc tcc cag 25638 Gln Asp Gly Ala Ser Asn Gly LeuThr Ala Pro Asn Gly Pro Ser Gln 8515 8520 8525 cag cgt gtc atc cgt caggcc ctg gcc aat gcg gga ctg acc ccg gcc 25686 Gln Arg Val Ile Arg GlnAla Leu Ala Asn Ala Gly Leu Thr Pro Ala 8530 8535 8540 gat gtc gac gcagtg gag ggc cac ggc acc ggg acc act ctg ggg gac 25734 Asp Val Asp AlaVal Glu Gly His Gly Thr Gly Thr Thr Leu Gly Asp 8545 8550 8555 8560 ccgatc gag gcc cag gca ctc ctg gcc gcc tac gga caa cac cgc ccc 25782 ProIle Glu Ala Gln Ala Leu Leu Ala Ala Tyr Gly Gln His Arg Pro 8565 85708575 cac cac cgc ccc ttg tgg ctg gga tcc ctc aaa tcc aac atc ggg cac25830 His His Arg Pro Leu Trp Leu Gly Ser Leu Lys Ser Asn Ile Gly His8580 8585 8590 gca cag gcc gcc gcg ggc gtg ggc gga gtc atc aag atg gtgatg gcc 25878 Ala Gln Ala Ala Ala Gly Val Gly Gly Val Ile Lys Met ValMet Ala 8595 8600 8605 ctg cgc aac ggg ctg ctg cca cag acc ctc cac gtggac gag ccc acc 25926 Leu Arg Asn Gly Leu Leu Pro Gln Thr Leu His ValAsp Glu Pro Thr 8610 8615 8620 ccc cag gtc gac tgg tcc aca ggc gca gtacaa ctc ctg aca caa ccg 25974 Pro Gln Val Asp Trp Ser Thr Gly Ala ValGln Leu Leu Thr Gln Pro 8625 8630 8635 8640 gtg ccc tgg ccc gcc gac ccggcc ggc cgg cca cgc cac gcc ggc gtg 26022 Val Pro Trp Pro Ala Asp ProAla Gly Arg Pro Arg His Ala Gly Val 8645 8650 8655 tca tca ttc ggc gtcagc ggc acc aac gcc cac atc atc ctc gaa gaa 26070 Ser Ser Phe Gly ValSer Gly Thr Asn Ala His Ile Ile Leu Glu Glu 8660 8665 8670 gca ccc actccc cag gac agc gat acc gac gac gaa ccg cct gcc aac 26118 Ala Pro ThrPro Gln Asp Ser Asp Thr Asp Asp Glu Pro Pro Ala Asn 8675 8680 8685 gcacca gcc ctg ccc cat ccc ctc cct ctt ccc gtg ccg gtg tcg gcg 26166 AlaPro Ala Leu Pro His Pro Leu Pro Leu Pro Val Pro Val Ser Ala 8690 86958700 agg tct gag gcc ggg ttg cgg gcg cag gca cag gcg ttg cgc cag tac26214 Arg Ser Glu Ala Gly Leu Arg Ala Gln Ala Gln Ala Leu Arg Gln Tyr8705 8710 8715 8720 gtg gca gcc cgc ccg gac atg tca cct gcc gac att ggtgcg ggt ctg 26262 Val Ala Ala Arg Pro Asp Met Ser Pro Ala Asp Ile GlyAla Gly Leu 8725 8730 8735 gcc cgc ggc cgg gcc gta ctg gaa cac cgc gccgtc atc ctg gcc gcg 26310 Ala Arg Gly Arg Ala Val Leu Glu His Arg AlaVal Ile Leu Ala Ala 8740 8745 8750 gac cgc gag gaa ctg gcg cag gca ctgaca gcc ctg gca gcc ggc gaa 26358 Asp Arg Glu Glu Leu Ala Gln Ala LeuThr Ala Leu Ala Ala Gly Glu 8755 8760 8765 ccc cac ccc cac atc acc acaggc cac acc cgg ggc ggt gac cgc ggc 26406 Pro His Pro His Ile Thr ThrGly His Thr Arg Gly Gly Asp Arg Gly 8770 8775 8780 ggc gtc gtc ttc gtcttc ccc gga cag ggc ggc cag tgg gcc ggg atg 26454 Gly Val Val Phe ValPhe Pro Gly Gln Gly Gly Gln Trp Ala Gly Met 8785 8790 8795 8800 ggc ctgacc ctg ctc acc tcc tca ccc gtg ttc gcc gaa cac atc gac 26502 Gly LeuThr Leu Leu Thr Ser Ser Pro Val Phe Ala Glu His Ile Asp 8805 8810 8815gca tgc gag aaa gcc ctc acc ccc tgg gtg ccc tgg tcc ctg acc gac 26550Ala Cys Glu Lys Ala Leu Thr Pro Trp Val Pro Trp Ser Leu Thr Asp 88208825 8830 atc ctg cac cgc gac ccc gac gac ccc gca tgg caa caa gcc gacgtg 26598 Ile Leu His Arg Asp Pro Asp Asp Pro Ala Trp Gln Gln Ala AspVal 8835 8840 8845 gtc cag ccc gtg ctc ttc agc atc atg gtc tcc ctc gccgcc ctg tgg 26646 Val Gln Pro Val Leu Phe Ser Ile Met Val Ser Leu AlaAla Leu Trp 8850 8855 8860 cgc tcc tac ggc atc gaa ccc gac gcg gtc ctcggc cac tcc cag gga 26694 Arg Ser Tyr Gly Ile Glu Pro Asp Ala Val LeuGly His Ser Gln Gly 8865 8870 8875 8880 gaa atc gcc gcc gcc cac atc tgcggc gca ctc agc ctg aaa gac gcc 26742 Glu Ile Ala Ala Ala His Ile CysGly Ala Leu Ser Leu Lys Asp Ala 8885 8890 8895 gcc aaa acc gtt gca ctgcgc agc cgc gca ctg gcc gcc gta cga ggc 26790 Ala Lys Thr Val Ala LeuArg Ser Arg Ala Leu Ala Ala Val Arg Gly 8900 8905 8910 cgg ggc gcc atggcc tca ctg ccc ctg ccc gcc cag gac gtg cag cag 26838 Arg Gly Ala MetAla Ser Leu Pro Leu Pro Ala Gln Asp Val Gln Gln 8915 8920 8925 ctc atttcc gaa cgg tgg gaa ggg cag ttg tgg gtg gca gcc ctc aac 26886 Leu IleSer Glu Arg Trp Glu Gly Gln Leu Trp Val Ala Ala Leu Asn 8930 8935 8940ggc ccc cac tcc acc acc gtc tcc ggc gac acc aag gcg gtg gat gag 26934Gly Pro His Ser Thr Thr Val Ser Gly Asp Thr Lys Ala Val Asp Glu 89458950 8955 8960 gtg ctg gcg cac tgc acc gac acc ggc cta cgg gcc aaa cgcatc ccc 26982 Val Leu Ala His Cys Thr Asp Thr Gly Leu Arg Ala Lys ArgIle Pro 8965 8970 8975 gtc gac tac gcc tcc cac tgc ccc cac gtc caa cccctc cac gac gaa 27030 Val Asp Tyr Ala Ser His Cys Pro His Val Gln ProLeu His Asp Glu 8980 8985 8990 ctc ctg cac ctg ctg gga gac atc acc ccccag ccg tcc acc gtg ccg 27078 Leu Leu His Leu Leu Gly Asp Ile Thr ProGln Pro Ser Thr Val Pro 8995 9000 9005 ttc ttc tcc acc gtg gaa ggc acctgg ctg gac acc aca acc ctg gac 27126 Phe Phe Ser Thr Val Glu Gly ThrTrp Leu Asp Thr Thr Thr Leu Asp 9010 9015 9020 gcc gcc tac tgg tac cgcaac ctc cac cag ccc gtc cgc ttc agc cac 27174 Ala Ala Tyr Trp Tyr ArgAsn Leu His Gln Pro Val Arg Phe Ser His 9025 9030 9035 9040 gcc atc cagacc ctg acc gac gac gga cac cgc gcc ttc atc gaa atc 27222 Ala Ile GlnThr Leu Thr Asp Asp Gly His Arg Ala Phe Ile Glu Ile 9045 9050 9055 agcccc cac ccc acc ctc gtc ccc gcc atc gaa gac acc acc gaa aac 27270 SerPro His Pro Thr Leu Val Pro Ala Ile Glu Asp Thr Thr Glu Asn 9060 90659070 acc acc gaa aac atc acc gcg acc ggc agc ctc cgc cgc ggc gac aac27318 Thr Thr Glu Asn Ile Thr Ala Thr Gly Ser Leu Arg Arg Gly Asp Asn9075 9080 9085 gac acc cac cgc ttc ctc acc gcc ctc gcc cac acc cac accacc ggc 27366 Asp Thr His Arg Phe Leu Thr Ala Leu Ala His Thr His ThrThr Gly 9090 9095 9100 atc ggc aca ccc acc acc tgg cac cac cac tac acccaa acc cac ccc 27414 Ile Gly Thr Pro Thr Thr Trp His His His Tyr ThrGln Thr His Pro 9105 9110 9115 9120 cac ccc aac ccc cac acc cac ctc gacctg ccc acc tac ccc ttc caa 27462 His Pro Asn Pro His Thr His Leu AspLeu Pro Thr Tyr Pro Phe Gln 9125 9130 9135 cac cag cac tac tgg ctc caacca ccc acc aca aca acc gac ctc acc 27510 His Gln His Tyr Trp Leu GlnPro Pro Thr Thr Thr Thr Asp Leu Thr 9140 9145 9150 acc acc ggc ctc accccc acc cac cac ccc ctc ctc acc gcc aca ctc 27558 Thr Thr Gly Leu ThrPro Thr His His Pro Leu Leu Thr Ala Thr Leu 9155 9160 9165 acc ctc gccgac aac aac aca caa cta ctc acc ggc cgc ctc tcc cta 27606 Thr Leu AlaAsp Asn Asn Thr Gln Leu Leu Thr Gly Arg Leu Ser Leu 9170 9175 9180 cgcacc cac ccc tgg ctc acc gac cac acc gtc gcc ggc atg gtc ctc 27654 ArgThr His Pro Trp Leu Thr Asp His Thr Val Ala Gly Met Val Leu 9185 91909195 9200 ctg ccg ggc acc gcg ctc ctc gaa ctc gcc ctc caa gcc ggc gaacgg 27702 Leu Pro Gly Thr Ala Leu Leu Glu Leu Ala Leu Gln Ala Gly GluArg 9205 9210 9215 gtg gac tgc cct cgg gtg gag gaa ctg acc ctg cac gcaccg ttg gtg 27750 Val Asp Cys Pro Arg Val Glu Glu Leu Thr Leu His AlaPro Leu Val 9220 9225 9230 atc ccg cac acc gag gac gtg acg ttg cag gtcacc gtt cgg gca gcc 27798 Ile Pro His Thr Glu Asp Val Thr Leu Gln ValThr Val Arg Ala Ala 9235 9240 9245 gat gag agt ggc cat cgc gcc ctc gcgatc cac tcg tac tcc ggc acc 27846 Asp Glu Ser Gly His Arg Ala Leu AlaIle His Ser Tyr Ser Gly Thr 9250 9255 9260 gcg tcg tcg gcg gac cgg gagtgg acc cgt cac gcc acg ggc ctc ctc 27894 Ala Ser Ser Ala Asp Arg GluTrp Thr Arg His Ala Thr Gly Leu Leu 9265 9270 9275 9280 aca cac cac gccgac acc gat cac cgt gcc gac acg cac acg gac gcg 27942 Thr His His AlaAsp Thr Asp His Arg Ala Asp Thr His Thr Asp Ala 9285 9290 9295 tgc cttggc ggg agc tgg ccc ccg ccc ggc gcg cag ccc atc gaa ctg 27990 Cys LeuGly Gly Ser Trp Pro Pro Pro Gly Ala Gln Pro Ile Glu Leu 9300 9305 9310ggc gac gtc tac ggt cgt atg gcg gcg gac tcg gac atc gcc tac ggg 28038Gly Asp Val Tyr Gly Arg Met Ala Ala Asp Ser Asp Ile Ala Tyr Gly 93159320 9325 ccg gtc ttc cag ggg ctg cac gcc gcc tgg agg ttc ggc gac gatgtc 28086 Pro Val Phe Gln Gly Leu His Ala Ala Trp Arg Phe Gly Asp AspVal 9330 9335 9340 ctg gcc gag gtg cgt ctg ccg gaa gag gct ctg cgc gatgct ccg gcg 28134 Leu Ala Glu Val Arg Leu Pro Glu Glu Ala Leu Arg AspAla Pro Ala 9345 9350 9355 9360 gcg gcc ttc ggt gtt cac ccg gcc ttg ctcgac gcg gcc ctg cac gcc 28182 Ala Ala Phe Gly Val His Pro Ala Leu LeuAsp Ala Ala Leu His Ala 9365 9370 9375 acg gcg ctc acc ccc cag aac ggggac ggc tcg acg gag aac gtc gcc 28230 Thr Ala Leu Thr Pro Gln Asn GlyAsp Gly Ser Thr Glu Asn Val Ala 9380 9385 9390 cag gag agc atg cct gaccgc gca gcc cac cag gcg cga ctg ccg ttc 28278 Gln Glu Ser Met Pro AspArg Ala Ala His Gln Ala Arg Leu Pro Phe 9395 9400 9405 agc tgg agc ggcgtg tcc ctg cac acg gcg ggc agt tcc gtg ttg cgc 28326 Ser Trp Ser GlyVal Ser Leu His Thr Ala Gly Ser Ser Val Leu Arg 9410 9415 9420 gta cggctg tcg cgc agt ccg cag cac ggt aat gcc gtg gcc ctc acc 28374 Val ArgLeu Ser Arg Ser Pro Gln His Gly Asn Ala Val Ala Leu Thr 9425 9430 94359440 gcg gcc gac gag gac ggt cgg ccg gtg gtg acg atc gag tcg ctc gcg28422 Ala Ala Asp Glu Asp Gly Arg Pro Val Val Thr Ile Glu Ser Leu Ala9445 9450 9455 ctg cgg ccg gtg tcc acc gag gag ctg cgc gcg gcc gcg gatcgt acg 28470 Leu Arg Pro Val Ser Thr Glu Glu Leu Arg Ala Ala Ala AspArg Thr 9460 9465 9470 ccc gag cac gag tcg ctc ttc cga ctg gac tgg gtttcc gta cca gtg 28518 Pro Glu His Glu Ser Leu Phe Arg Leu Asp Trp ValSer Val Pro Val 9475 9480 9485 ccc gcc aac gcc cct tcg ccc acc gcg gaccgg ccc tgg gcg gtc atc 28566 Pro Ala Asn Ala Pro Ser Pro Thr Ala AspArg Pro Trp Ala Val Ile 9490 9495 9500 ggc gcg ggc ctt ccc cac ctg cccggc ctg acg gag cac gag cac gtg 28614 Gly Ala Gly Leu Pro His Leu ProGly Leu Thr Glu His Glu His Val 9505 9510 9515 9520 acc gcg tat gac gagccg gcg gac ctg ctt ctg gct ctg gac cgc ggt 28662 Thr Ala Tyr Asp GluPro Ala Asp Leu Leu Leu Ala Leu Asp Arg Gly 9525 9530 9535 gct ccg ccgccc ggt gtg ctg gtc gta ggt ggt gtc gcc cac acc gaa 28710 Ala Pro ProPro Gly Val Leu Val Val Gly Gly Val Ala His Thr Glu 9540 9545 9550 gcccgg gag tat tcc gcc gaa gcc ccc ggg gag cgc ggg acc gag gcc 28758 AlaArg Glu Tyr Ser Ala Glu Ala Pro Gly Glu Arg Gly Thr Glu Ala 9555 95609565 tgc gag gcc cgg ccg gac gtc gtg cac gtg ggc gtc gtg cac acg gct28806 Cys Glu Ala Arg Pro Asp Val Val His Val Gly Val Val His Thr Ala9570 9575 9580 gcc gtg cac gcg gct gcc gcg cag atg ttg gcc agg ctc caggcc tgg 28854 Ala Val His Ala Ala Ala Ala Gln Met Leu Ala Arg Leu GlnAla Trp 9585 9590 9595 9600 ctg ggc gac gag cgc ctc gca gac agc cgg ctgctc gtc ctg acg tgc 28902 Leu Gly Asp Glu Arg Leu Ala Asp Ser Arg LeuLeu Val Leu Thr Cys 9605 9610 9615 ggc gcg gtc gcc cgc gcc tcc ggc gacgat gcg acg gac ctg ccc ggg 28950 Gly Ala Val Ala Arg Ala Ser Gly AspAsp Ala Thr Asp Leu Pro Gly 9620 9625 9630 gcc gcc gtg tgg ggg ctg gtgcgt tcg gcg cag tcc gag cac ccg gac 28998 Ala Ala Val Trp Gly Leu ValArg Ser Ala Gln Ser Glu His Pro Asp 9635 9640 9645 cgc atc acg ctg ctggac ttc gag cgg ggc aca gag gcg gag ccc ggt 29046 Arg Ile Thr Leu LeuAsp Phe Glu Arg Gly Thr Glu Ala Glu Pro Gly 9650 9655 9660 cag ctg gcgacg gcg ctg aac tgc ggg gag cgg cag ctt gcc gtc cgc 29094 Gln Leu AlaThr Ala Leu Asn Cys Gly Glu Arg Gln Leu Ala Val Arg 9665 9670 9675 9680ccc gga ggg ctg ttc acg cca cgg ctg gtg cgc gcg cca cgt gtc gcc 29142Pro Gly Gly Leu Phe Thr Pro Arg Leu Val Arg Ala Pro Arg Val Ala 96859690 9695 gac gcc gta ccc gcc gta ccc gcc gtg gcc gta ccg tca gcg ggtcac 29190 Asp Ala Val Pro Ala Val Pro Ala Val Ala Val Pro Ser Ala GlyHis 9700 9705 9710 gca gcc gta ccg gca gcg ggt ccc ttc ctt ccg ggc ggaacg gtg ctg 29238 Ala Ala Val Pro Ala Ala Gly Pro Phe Leu Pro Gly GlyThr Val Leu 9715 9720 9725 atc acc ggc gga acc ggt gtc ctg ggc cgg ctcgtg gcc cgg cat ctg 29286 Ile Thr Gly Gly Thr Gly Val Leu Gly Arg LeuVal Ala Arg His Leu 9730 9735 9740 gtg gag gcg cac ggc gta cgg cat ctgttg ctg gcg ggt cgg cgc gga 29334 Val Glu Ala His Gly Val Arg His LeuLeu Leu Ala Gly Arg Arg Gly 9745 9750 9755 9760 ccg gac gcc gag ggt gcgccg gag ttg cgg gcg gag ctc ggt ggg ctc 29382 Pro Asp Ala Glu Gly AlaPro Glu Leu Arg Ala Glu Leu Gly Gly Leu 9765 9770 9775 ggc gcg acg gtggag gtc gtc gcc tgc gac gcg gcg gac cgg cag cag 29430 Gly Ala Thr ValGlu Val Val Ala Cys Asp Ala Ala Asp Arg Gln Gln 9780 9785 9790 ctg gccgac ctg ctg aca cgg atc ccc gac gat cgg ccg ctg acc ggt 29478 Leu AlaAsp Leu Leu Thr Arg Ile Pro Asp Asp Arg Pro Leu Thr Gly 9795 9800 9805gtc gtg cac agt gcg ggc atc ctg gac gac ggc gtg atc acg tcg ctg 29526Val Val His Ser Ala Gly Ile Leu Asp Asp Gly Val Ile Thr Ser Leu 98109815 9820 tcg ccg gag cgg ctc ggg gcc gtc ctc cgg gcc aag gcg gac gctgcg 29574 Ser Pro Glu Arg Leu Gly Ala Val Leu Arg Ala Lys Ala Asp AlaAla 9825 9830 9835 9840 ctg ctt ctc gac gag ctg acg cgc ggg gca gag ctgtcg gct ttc gtc 29622 Leu Leu Leu Asp Glu Leu Thr Arg Gly Ala Glu LeuSer Ala Phe Val 9845 9850 9855 atg ttc tcc tcc gcg tcg gcg gtg gtc ggctcg ccc ggg cag ggc aac 29670 Met Phe Ser Ser Ala Ser Ala Val Val GlySer Pro Gly Gln Gly Asn 9860 9865 9870 tac gcc gcc gcc aac gcc gtc ctcgac ttc ctt gct cat cgc cgc cgc 29718 Tyr Ala Ala Ala Asn Ala Val LeuAsp Phe Leu Ala His Arg Arg Arg 9875 9880 9885 gcc gag ggg ctg ccc gccgtc tct ctc gcc tgg ggc ctg tgg gaa gag 29766 Ala Glu Gly Leu Pro AlaVal Ser Leu Ala Trp Gly Leu Trp Glu Glu 9890 9895 9900 ggc aca ggg atgacg ggc cac ctc gac gtc gac gac cat gcg cgg atc 29814 Gly Thr Gly MetThr Gly His Leu Asp Val Asp Asp His Ala Arg Ile 9905 9910 9915 9920 agccgc gcg gga atg cgg ccg ctg ccg act gcc gag gct ctg gcg ctg 29862 SerArg Ala Gly Met Arg Pro Leu Pro Thr Ala Glu Ala Leu Ala Leu 9925 99309935 ttc gac gcg gcc ttg gcc gac ggc gag ccg ttc ctg atg ccg gct cgg29910 Phe Asp Ala Ala Leu Ala Asp Gly Glu Pro Phe Leu Met Pro Ala Arg9940 9945 9950 ctc gac ctc acg gcc gta cgg tct ggt gcc gcg tcc gca ccggtg ccg 29958 Leu Asp Leu Thr Ala Val Arg Ser Gly Ala Ala Ser Ala ProVal Pro 9955 9960 9965 ccg ctg ctg caa ggt ctg ctt cag ctg cct cgg tcccgc tcg gcc gcc 30006 Pro Leu Leu Gln Gly Leu Leu Gln Leu Pro Arg SerArg Ser Ala Ala 9970 9975 9980 gcg gcc ccc ggc cat ggg gcc ccg gcg gcggac gag gcg gcg gcc tgg 30054 Ala Ala Pro Gly His Gly Ala Pro Ala AlaAsp Glu Ala Ala Ala Trp 9985 9990 9995 10000 cgt gag cgt ctg gcc cgg cagagt gcc ggt gag cgc agg cag gcg ctg 30102 Arg Glu Arg Leu Ala Arg GlnSer Ala Gly Glu Arg Arg Gln Ala Leu 10005 10010 10015 ctg cgc ctg gtgcgg tcg cat gtc gcg gcg gtg ctc ggc cat agc ggt 30150 Leu Arg Leu ValArg Ser His Val Ala Ala Val Leu Gly His Ser Gly 10020 10025 10030 gccgac gga atc gac gca tcg cgg gcg ttc cgc gag ctg ggg ttc gac 30198 AlaAsp Gly Ile Asp Ala Ser Arg Ala Phe Arg Glu Leu Gly Phe Asp 10035 1004010045 tcg ctc acg gcg gtc gag ctg cgc aac cgt ctc acg gcc gcg acg ggc30246 Ser Leu Thr Ala Val Glu Leu Arg Asn Arg Leu Thr Ala Ala Thr Gly10050 10055 10060 ctg cgg ctg cgg gcc acg ctg gcc ttc gat ttc ccg accccg gca gcg 30294 Leu Arg Leu Arg Ala Thr Leu Ala Phe Asp Phe Pro ThrPro Ala Ala 10065 10070 10075 10080 ctg gcc gag cac ttg ggc gag cgt ctgctt ccc gac cag gag gcc acg 30342 Leu Ala Glu His Leu Gly Glu Arg LeuLeu Pro Asp Gln Glu Ala Thr 10085 10090 10095 ggc gag caa gcc ggc gatcag ctc tcc ggc ggc agc gag gag gac gta 30390 Gly Glu Gln Ala Gly AspGln Leu Ser Gly Gly Ser Glu Glu Asp Val 10100 10105 10110 cgc agc ctcctg acg tcc att ccg atc ggc agg ctg cgg gac gcg ggg 30438 Arg Ser LeuLeu Thr Ser Ile Pro Ile Gly Arg Leu Arg Asp Ala Gly 10115 10120 10125ctc ctc ggg ccc ctg ctc acg ctc gcg gac acg ggc cgc ggc gcc tcg 30486Leu Leu Gly Pro Leu Leu Thr Leu Ala Asp Thr Gly Arg Gly Ala Ser 1013010135 10140 ggc gcc gcc gca ggt ccg gag gac gcg ccg ccc tcc ggc cag gacaca 30534 Gly Ala Ala Ala Gly Pro Glu Asp Ala Pro Pro Ser Gly Gln AspThr 10145 10150 10155 10160 ccg gct ccc gtc tcg atc gac gag atg gac atcgac gac ctg atg gat 30582 Pro Ala Pro Val Ser Ile Asp Glu Met Asp IleAsp Asp Leu Met Asp 10165 10170 10175 ctg gcg cac ggg cat ggc acc gcaccc gcc cgt gag ccc gcc gac gca 30630 Leu Ala His Gly His Gly Thr AlaPro Ala Arg Glu Pro Ala Asp Ala 10180 10185 10190 gag gac tcg tcg tcatca cga aac cgg aca cac cac aca cac gaa ggt 30678 Glu Asp Ser Ser SerSer Arg Asn Arg Thr His His Thr His Glu Gly 10195 10200 10205 gag acagcg tga 30690 Glu Thr Ala 10210 2 31422 DNA Streptomyces avermitilis CDS(1)..(14643) CDS (14824)..(31419) 2 atg gct aac gag gaa aag ctc cgc gactat ctc aag cgc gtt act gcc 48 Met Ala Asn Glu Glu Lys Leu Arg Asp TyrLeu Lys Arg Val Thr Ala 1 5 10 15 gat ctc ctc aat gtg cgg cgt cga cttcag cag att gaa tcg ggc gag 96 Asp Leu Leu Asn Val Arg Arg Arg Leu GlnGln Ile Glu Ser Gly Glu 20 25 30 cag gag ccg att gca att gtg ggg atg gcgtgc cgt ttt ccg ggg ggt 144 Gln Glu Pro Ile Ala Ile Val Gly Met Ala CysArg Phe Pro Gly Gly 35 40 45 gtg gag tcg gcg gag gat ttc tgg gag ttg attgcg tcg ggt cgg gat 192 Val Glu Ser Ala Glu Asp Phe Trp Glu Leu Ile AlaSer Gly Arg Asp 50 55 60 gcg gtg ggg gag ttt ccg gtc gac cgg ggt tgg gacgtg gag gct ttc 240 Ala Val Gly Glu Phe Pro Val Asp Arg Gly Trp Asp ValGlu Ala Phe 65 70 75 80 tat gat ccg gag ccg ggg cgg gcg ggt tcg tcg tatacg cgc cgg ggc 288 Tyr Asp Pro Glu Pro Gly Arg Ala Gly Ser Ser Tyr ThrArg Arg Gly 85 90 95 ggt ttc ctg gag ggt gcg gcg gag ttc gat gcg ggg tttttc ggg atc 336 Gly Phe Leu Glu Gly Ala Ala Glu Phe Asp Ala Gly Phe PheGly Ile 100 105 110 agt ccg cgt gag gcg ttg gcg atg gat ccg cag cag cggttg atg ctg 384 Ser Pro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln Arg LeuMet Leu 115 120 125 gag gtg tcc tgg gag gcg ttg gag cgg gcg ggc atc gacccc gcc acg 432 Glu Val Ser Trp Glu Ala Leu Glu Arg Ala Gly Ile Asp ProAla Thr 130 135 140 ttg cgc ggc agc cgg acg ggc gtc ttc gcc ggc ctc atgtcc cag gac 480 Leu Arg Gly Ser Arg Thr Gly Val Phe Ala Gly Leu Met SerGln Asp 145 150 155 160 tac gcg acc cgt ctg ctc tcg gtc ccc gac gac ctggcc ggc tac ctg 528 Tyr Ala Thr Arg Leu Leu Ser Val Pro Asp Asp Leu AlaGly Tyr Leu 165 170 175 ggc aac ggc aac gcg gga agc atc ctg tcc gga cgcgtc gcc tac acc 576 Gly Asn Gly Asn Ala Gly Ser Ile Leu Ser Gly Arg ValAla Tyr Thr 180 185 190 ttc ggc ttc gag ggc ccc gcg gtg acg gtc gac acggcg tgc tcg tcg 624 Phe Gly Phe Glu Gly Pro Ala Val Thr Val Asp Thr AlaCys Ser Ser 195 200 205 tcg ctg gtg gca ctg cac ctc gcc tgc cag tca ctgcgc acc ggt gag 672 Ser Leu Val Ala Leu His Leu Ala Cys Gln Ser Leu ArgThr Gly Glu 210 215 220 tcc tcc ttc gcc ctc gcc gga ggc gtg acg gtc atgtcc acc ccg ggc 720 Ser Ser Phe Ala Leu Ala Gly Gly Val Thr Val Met SerThr Pro Gly 225 230 235 240 atg ttc gtg gag ttc tcg cgg cag cgg ggt ctgtcg ccg gac ggc cgg 768 Met Phe Val Glu Phe Ser Arg Gln Arg Gly Leu SerPro Asp Gly Arg 245 250 255 tgc aag gcg tac gcg tcg gct gcc gac ggc accggc atg tcc gag ggc 816 Cys Lys Ala Tyr Ala Ser Ala Ala Asp Gly Thr GlyMet Ser Glu Gly 260 265 270 gtg ggg att ttg ctg ctg gag cgg ctg tcc gaggct gaa cgt cgt ggt 864 Val Gly Ile Leu Leu Leu Glu Arg Leu Ser Glu AlaGlu Arg Arg Gly 275 280 285 cat cgg gtt ttg gcg gtg gtg cgg ggg agt gcggtg aat cag gac ggt 912 His Arg Val Leu Ala Val Val Arg Gly Ser Ala ValAsn Gln Asp Gly 290 295 300 gcg tcg aat ggg ttg acg gcg ccg aat ggt ccgtcg cag cag cgg gtg 960 Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro SerGln Gln Arg Val 305 310 315 320 att cgg cag gcg ttg gcg tgt gcg ggg ttgtct gtg gcg gat gtg gat 1008 Ile Arg Gln Ala Leu Ala Cys Ala Gly Leu SerVal Ala Asp Val Asp 325 330 335 gtg gtg gag ggg cac ggg acg ggc acg acgctg ggt gat ccg atc gag 1056 Val Val Glu Gly His Gly Thr Gly Thr Thr LeuGly Asp Pro Ile Glu 340 345 350 gcg cag gcg ttg ctc gcc acg tac ggg cagcgg gcc ggt gac acg ccg 1104 Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln ArgAla Gly Asp Thr Pro 355 360 365 gtg tgg ttg ggg tcg gtg aag tcg aac atcggg cat gcg cag gct gct 1152 Val Trp Leu Gly Ser Val Lys Ser Asn Ile GlyHis Ala Gln Ala Ala 370 375 380 gcg ggt gtg gcg ggt gtg atc aag atg gtgatg gcg ttg cgg gcg ggg 1200 Ala Gly Val Ala Gly Val Ile Lys Met Val MetAla Leu Arg Ala Gly 385 390 395 400 gtg ttg ccg cgg acg ttg cat gtg gatgag ccg tcg tcg cag gtg gat 1248 Val Leu Pro Arg Thr Leu His Val Asp GluPro Ser Ser Gln Val Asp 405 410 415 tgg tcg agt ggg tcg gtt cgt gtg ttggcg gat gag gtg gag tgg ccg 1296 Trp Ser Ser Gly Ser Val Arg Val Leu AlaAsp Glu Val Glu Trp Pro 420 425 430 ggg gtg gag ggt cgg ctg cgg cgt gcgggg gtg tct gcg ttc ggg gtg 1344 Gly Val Glu Gly Arg Leu Arg Arg Ala GlyVal Ser Ala Phe Gly Val 435 440 445 agt ggg acg aat gcg cat gtg att ttggag gag gcg tcg ggg ggc gcg 1392 Ser Gly Thr Asn Ala His Val Ile Leu GluGlu Ala Ser Gly Gly Ala 450 455 460 ggt ggg ggt gcg ggc cgg ctg cag gagttg ggt ccg ggg gtg gtg tcg 1440 Gly Gly Gly Ala Gly Arg Leu Gln Glu LeuGly Pro Gly Val Val Ser 465 470 475 480 ggt tcg ggg gtg gtg ccg tgg gtggtg tcg gcg cgg tcg gag ttg gcg 1488 Gly Ser Gly Val Val Pro Trp Val ValSer Ala Arg Ser Glu Leu Ala 485 490 495 ttg cgg ggg cag gcg cgt cgg ttgcgt ggg gtt gtg gcg gtt ggt ggg 1536 Leu Arg Gly Gln Ala Arg Arg Leu ArgGly Val Val Ala Val Gly Gly 500 505 510 ggt gcg gat ggt gtg ggg gtg agtccg gct ggg gtc ggg cgg gct ttg 1584 Gly Ala Asp Gly Val Gly Val Ser ProAla Gly Val Gly Arg Ala Leu 515 520 525 gtg tcg gag cgg tcg gtg ttc gagcat cgt gcg gtg gtc gtg gcc gag 1632 Val Ser Glu Arg Ser Val Phe Glu HisArg Ala Val Val Val Ala Glu 530 535 540 gac cgc gac gag ttc ctg cac gcactc gac gca ctg gcc ggc ggc cgc 1680 Asp Arg Asp Glu Phe Leu His Ala LeuAsp Ala Leu Ala Gly Gly Arg 545 550 555 560 ccc gtg ccc ggc gtc gtc gaggga cga acc acc tcg ggc gaa ctc gcc 1728 Pro Val Pro Gly Val Val Glu GlyArg Thr Thr Ser Gly Glu Leu Ala 565 570 575 gta ctc ttc gcc ggg cag ggaacc cag cgc gca ggc atg ggc cgc gaa 1776 Val Leu Phe Ala Gly Gln Gly ThrGln Arg Ala Gly Met Gly Arg Glu 580 585 590 ctg tac gag gcg tac ccc gtcttc gcc cag gcc atc gac gag atc tgc 1824 Leu Tyr Glu Ala Tyr Pro Val PheAla Gln Ala Ile Asp Glu Ile Cys 595 600 605 gcg gag gcc gac acc gcc cgcacc gac ccc ggt gcc cct ggg ctg cgg 1872 Ala Glu Ala Asp Thr Ala Arg ThrAsp Pro Gly Ala Pro Gly Leu Arg 610 615 620 gac gta ctc ttc gca ccg caggac tct ccc gaa ggc cgg ctg atc gag 1920 Asp Val Leu Phe Ala Pro Gln AspSer Pro Glu Gly Arg Leu Ile Glu 625 630 635 640 gac acg ggt ttc gcc cagccc gcc ctg ttc gcc ttc gag gtg gcg ctg 1968 Asp Thr Gly Phe Ala Gln ProAla Leu Phe Ala Phe Glu Val Ala Leu 645 650 655 ttc cgg ctg ctg gag acctgg ggt ctg acg ccc gac tac gtc ctc ggc 2016 Phe Arg Leu Leu Glu Thr TrpGly Leu Thr Pro Asp Tyr Val Leu Gly 660 665 670 cat tcc gtc ggt gaa ctggcg gcc gcc cat gtc gcc ggg atg ctc tgc 2064 His Ser Val Gly Glu Leu AlaAla Ala His Val Ala Gly Met Leu Cys 675 680 685 ctt gcc gac gcg gtg gcactg gtg gtc gca cga ggc cgc ctg atg caa 2112 Leu Ala Asp Ala Val Ala LeuVal Val Ala Arg Gly Arg Leu Met Gln 690 695 700 ggg ctc ccg tcc ggc ggagcc atg gtg gcc atc gag gcg tcc gag gac 2160 Gly Leu Pro Ser Gly Gly AlaMet Val Ala Ile Glu Ala Ser Glu Asp 705 710 715 720 gag atc ctc ccg ctgccc gac gaa tac gca tcc cgg gtc gcg cac gcc 2208 Glu Ile Leu Pro Leu ProAsp Glu Tyr Ala Ser Arg Val Ala His Ala 725 730 735 gcg gtg aac ggg ccgcgg tcg atc gtc ctc tcc ggg gac gag gac gcg 2256 Ala Val Asn Gly Pro ArgSer Ile Val Leu Ser Gly Asp Glu Asp Ala 740 745 750 gtc ctg gac ctc gcgcag caa tgg gcg gca cga ggc cgc cgc acc cgg 2304 Val Leu Asp Leu Ala GlnGln Trp Ala Ala Arg Gly Arg Arg Thr Arg 755 760 765 cgg ctg cgg acc agccac gcc ttc cac tcg ccg cac atg gac gcc atg 2352 Arg Leu Arg Thr Ser HisAla Phe His Ser Pro His Met Asp Ala Met 770 775 780 ttg ggc gac ttc cgccgc gcg gcc gag cag gtc acc ttc agc gcc ccg 2400 Leu Gly Asp Phe Arg ArgAla Ala Glu Gln Val Thr Phe Ser Ala Pro 785 790 795 800 cgg att ccc gtcgtc tcc aac gtc acc ggc gcg ccc ctc ccc gcc gag 2448 Arg Ile Pro Val ValSer Asn Val Thr Gly Ala Pro Leu Pro Ala Glu 805 810 815 acc atg tgc accccg gac tac tgg gtc gaa cac gcc cgc agc acg gtc 2496 Thr Met Cys Thr ProAsp Tyr Trp Val Glu His Ala Arg Ser Thr Val 820 825 830 cgt ttc gcg gacggc atc tca tgg ctt cag gaa cag ggc gtc acc acc 2544 Arg Phe Ala Asp GlyIle Ser Trp Leu Gln Glu Gln Gly Val Thr Thr 835 840 845 tgc ctc gaa atcggc ccc gac ggc acg ctg tcg gcc ctc gca cag gac 2592 Cys Leu Glu Ile GlyPro Asp Gly Thr Leu Ser Ala Leu Ala Gln Asp 850 855 860 tcg ctc agt gcaccg gcc cgc gcc atc ccc gcc ctg cgg ccg gac cag 2640 Ser Leu Ser Ala ProAla Arg Ala Ile Pro Ala Leu Arg Pro Asp Gln 865 870 875 880 ccg gag gcacgg tcg gtc atg acc gcc ctg gcg gag ttg ttc gtg gct 2688 Pro Glu Ala ArgSer Val Met Thr Ala Leu Ala Glu Leu Phe Val Ala 885 890 895 ggg acg gcggtt gag tgg gcc ggt gtg ttc gag ggg act gct cgc gag 2736 Gly Thr Ala ValGlu Trp Ala Gly Val Phe Glu Gly Thr Ala Arg Glu 900 905 910 gtc ggt gatgga tgc ggg gtg gag ctg ccg acg tat gcg ttt gag cgg 2784 Val Gly Asp GlyCys Gly Val Glu Leu Pro Thr Tyr Ala Phe Glu Arg 915 920 925 gag cga ttttgg ctg gac gtg gag gag gga tct gcg gga ggt tcc ggg 2832 Glu Arg Phe TrpLeu Asp Val Glu Glu Gly Ser Ala Gly Gly Ser Gly 930 935 940 gtt tcc gggatg tgg ggt ggt ccg ttg tgg gag gcg gtc gag tgt ggt 2880 Val Ser Gly MetTrp Gly Gly Pro Leu Trp Glu Ala Val Glu Cys Gly 945 950 955 960 gat gcgggg gtg gtg gca tcg ctc ctt ggg gtg gat gag ggg gcg tcg 2928 Asp Ala GlyVal Val Ala Ser Leu Leu Gly Val Asp Glu Gly Ala Ser 965 970 975 ctg ggtgcg gtg gtg tcg gcg ttg ggg gaa tgg ggg cgg gta cgg cac 2976 Leu Gly AlaVal Val Ser Ala Leu Gly Glu Trp Gly Arg Val Arg His 980 985 990 gag cgtgaa gtg gtg gac ggg tgg cgc tat cgg gag gtg tgg cga ccc 3024 Glu Arg GluVal Val Asp Gly Trp Arg Tyr Arg Glu Val Trp Arg Pro 995 1000 1005 gtttcg ggc ggt ggt gta ggg ggg ctg tcg ggc gcg tgg ctg gtg gtg 3072 Val SerGly Gly Gly Val Gly Gly Leu Ser Gly Ala Trp Leu Val Val 1010 1015 1020tcc gag ggc gag gcg ggc ccg gtt gat gtg gtg gcg gag ggg ttg gag 3120 SerGlu Gly Glu Ala Gly Pro Val Asp Val Val Ala Glu Gly Leu Glu 1025 10301035 1040 cgg tgt ggg gcg cga gtg gtt cgg gtg gag gtg gaa gcg ggg tgtgtg 3168 Arg Cys Gly Ala Arg Val Val Arg Val Glu Val Glu Ala Gly Cys Val1045 1050 1055 agc agg gaa gtg ttg gcc ggc cac ctg cgt gag gcg gtc gatggt gag 3216 Ser Arg Glu Val Leu Ala Gly His Leu Arg Glu Ala Val Asp GlyGlu 1060 1065 1070 gct gtc ggc ggt gtc gtc tcc ctt gtg ggc tgg ggg agtggc gtc gtg 3264 Ala Val Gly Gly Val Val Ser Leu Val Gly Trp Gly Ser GlyVal Val 1075 1080 1085 cag gcg gga gtg gcg tct gtg ggg ttg gtg cag gcgctg ggt gat gtg 3312 Gln Ala Gly Val Ala Ser Val Gly Leu Val Gln Ala LeuGly Asp Val 1090 1095 1100 ggc gtg ggg gcg cgg ctg tgg tgt gtg acg ggcggg gcc gtg tcg gtg 3360 Gly Val Gly Ala Arg Leu Trp Cys Val Thr Gly GlyAla Val Ser Val 1105 1110 1115 1120 ggg ggc cgg gat gct gtg tgg ggg ccggcc tcg ggt gtg gtg tgg ggg 3408 Gly Gly Arg Asp Ala Val Trp Gly Pro AlaSer Gly Val Val Trp Gly 1125 1130 1135 ctg ggc cgt gtg gtg ggg gcg gaggca ccg gac cgc tgg ggt ggg ctg 3456 Leu Gly Arg Val Val Gly Ala Glu AlaPro Asp Arg Trp Gly Gly Leu 1140 1145 1150 gtt gat gtg ccg gag ctc gtggat gag cgg gtg gtc gat ggg ttg gta 3504 Val Asp Val Pro Glu Leu Val AspGlu Arg Val Val Asp Gly Leu Val 1155 1160 1165 ggt gtg ctg gcg ggt gtgggg gga ggg ggt gag agt gag ttt gcc gtg 3552 Gly Val Leu Ala Gly Val GlyGly Gly Gly Glu Ser Glu Phe Ala Val 1170 1175 1180 cgg tct tcg ggg gcgttt gtg cgg cgg ttg gtg cgg gcg ccg ttg gag 3600 Arg Ser Ser Gly Ala PheVal Arg Arg Leu Val Arg Ala Pro Leu Glu 1185 1190 1195 1200 gag gcc gtcgcg gag cgg gag tgg cgg ccc cgc ggc acc gta ctc gtc 3648 Glu Ala Val AlaGlu Arg Glu Trp Arg Pro Arg Gly Thr Val Leu Val 1205 1210 1215 acc ggaggc acc ggc gag ttg ggt gcg cac gtc gcc cgg tgg atg gcc 3696 Thr Gly GlyThr Gly Glu Leu Gly Ala His Val Ala Arg Trp Met Ala 1220 1225 1230 cggcgt ggc gcc gaa cac ctg ctg ctg gtg agc cga cgc ggg gag agc 3744 Arg ArgGly Ala Glu His Leu Leu Leu Val Ser Arg Arg Gly Glu Ser 1235 1240 1245gcc cag gga gtc gaa gaa ctc cga gcg gac ttg atg ggc ttg ggc gcg 3792 AlaGln Gly Val Glu Glu Leu Arg Ala Asp Leu Met Gly Leu Gly Ala 1250 12551260 cgg gtg tcg gtg gtg gcg tgt gat gcg gcg gac cgt gag gcg ttg gcg3840 Arg Val Ser Val Val Ala Cys Asp Ala Ala Asp Arg Glu Ala Leu Ala1265 1270 1275 1280 gag gtg ttg cgg tcg gcc gtt ccg gcg gag tgc ccg ctgggt gtg gtg 3888 Glu Val Leu Arg Ser Ala Val Pro Ala Glu Cys Pro Leu GlyVal Val 1285 1290 1295 gtg cat gcc gcg gga gtt gtg gat gac ggg gtg ttggag ggg ttg tcg 3936 Val His Ala Ala Gly Val Val Asp Asp Gly Val Leu GluGly Leu Ser 1300 1305 1310 tcc gag cgt gtc acg ggg gtg ctg cgg gcg aaggcg ctg gcg gcc tgg 3984 Ser Glu Arg Val Thr Gly Val Leu Arg Ala Lys AlaLeu Ala Ala Trp 1315 1320 1325 aat ctg cat gag ttg acg cgg ggg gcg gatctt tcg ggg ttc gtg gtg 4032 Asn Leu His Glu Leu Thr Arg Gly Ala Asp LeuSer Gly Phe Val Val 1330 1335 1340 ttc tcg tcg gct gcg gcg acg ttc gggccg gcg gga cag ggg agt tac 4080 Phe Ser Ser Ala Ala Ala Thr Phe Gly ProAla Gly Gln Gly Ser Tyr 1345 1350 1355 1360 gcg gcg gcg aac gcg tat gtggag gca atc gtt cgg cac cgg cgt ggt 4128 Ala Ala Ala Asn Ala Tyr Val GluAla Ile Val Arg His Arg Arg Gly 1365 1370 1375 gag ggc ctg ccg ggg ttggcg gtg gcg tgg ggt ccg tgg gct ggt ggg 4176 Glu Gly Leu Pro Gly Leu AlaVal Ala Trp Gly Pro Trp Ala Gly Gly 1380 1385 1390 ggg atg gcg gag ggggcc gtg ggg cag atg cgg cgt cgg ggt ctg gcg 4224 Gly Met Ala Glu Gly AlaVal Gly Gln Met Arg Arg Arg Gly Leu Ala 1395 1400 1405 gcg atg acg ccggag acg gcg ctg gtg gca ctg ggc cag gcg ttg gac 4272 Ala Met Thr Pro GluThr Ala Leu Val Ala Leu Gly Gln Ala Leu Asp 1410 1415 1420 cat gac gagacc tgt gtg acg gtc gcc gac atc gac tgg gac cga ttc 4320 His Asp Glu ThrCys Val Thr Val Ala Asp Ile Asp Trp Asp Arg Phe 1425 1430 1435 1440 accgcc aac tcc ctc ccc ggc tcc cga ctc tcg ccc ctc atc agc gac 4368 Thr AlaAsn Ser Leu Pro Gly Ser Arg Leu Ser Pro Leu Ile Ser Asp 1445 1450 1455atc ccc gaa gca cgc ctc gcc cgg gaa acc acc gga ctc gac acc gcc 4416 IlePro Glu Ala Arg Leu Ala Arg Glu Thr Thr Gly Leu Asp Thr Ala 1460 14651470 acc gca tcc ccc gac tcg ttc tcc gca cgg ctc aag gcc atg gac acc4464 Thr Ala Ser Pro Asp Ser Phe Ser Ala Arg Leu Lys Ala Met Asp Thr1475 1480 1485 gcc gag cag gaa cgt gcg ctt ctc gac ctg gtc cgt acg tacgcg gcg 4512 Ala Glu Gln Glu Arg Ala Leu Leu Asp Leu Val Arg Thr Tyr AlaAla 1490 1495 1500 acc gtg ctc gga cac agc acc ccc acc gcc gta cgc cctgag cga gcc 4560 Thr Val Leu Gly His Ser Thr Pro Thr Ala Val Arg Pro GluArg Ala 1505 1510 1515 1520 ttc cgc gac ctg ggc ttc gtc tcc gtg agc gccgtc gaa ctg cgc aac 4608 Phe Arg Asp Leu Gly Phe Val Ser Val Ser Ala ValGlu Leu Arg Asn 1525 1530 1535 cgc ctc aac gcc gtc acc ggg ctc ctc ctgccc acc acg ctg atc ttc 4656 Arg Leu Asn Ala Val Thr Gly Leu Leu Leu ProThr Thr Leu Ile Phe 1540 1545 1550 gac tac ccc act ccc tcc gcg ctg gccgga tac ctc aag gaa cag ctg 4704 Asp Tyr Pro Thr Pro Ser Ala Leu Ala GlyTyr Leu Lys Glu Gln Leu 1555 1560 1565 gag gag ggc gcg ggc ggc cag cgtgac att gct cct ccg gtc ccg gcg 4752 Glu Glu Gly Ala Gly Gly Gln Arg AspIle Ala Pro Pro Val Pro Ala 1570 1575 1580 tcg cgt gtc gac gtt gac gagccg att gcg att gtg ggg atg gcg tgc 4800 Ser Arg Val Asp Val Asp Glu ProIle Ala Ile Val Gly Met Ala Cys 1585 1590 1595 1600 cgt ttt ccg ggg ggtgtg gag tcg gcg gag gac ttg tgg gaa ctg gtc 4848 Arg Phe Pro Gly Gly ValGlu Ser Ala Glu Asp Leu Trp Glu Leu Val 1605 1610 1615 gcg tcg ggt cgggat gcg gtg gga gag ttt ccg gtc gac cgg ggt tgg 4896 Ala Ser Gly Arg AspAla Val Gly Glu Phe Pro Val Asp Arg Gly Trp 1620 1625 1630 gac gtg gaggct ttc tat gat ccg gag ccg ggg cgg gcg ggt tcg tcg 4944 Asp Val Glu AlaPhe Tyr Asp Pro Glu Pro Gly Arg Ala Gly Ser Ser 1635 1640 1645 tat acgcgc cgg ggc ggt ttc ctg gag ggt gcg gcg gag ttc gat gcg 4992 Tyr Thr ArgArg Gly Gly Phe Leu Glu Gly Ala Ala Glu Phe Asp Ala 1650 1655 1660 gggttt ttc ggg atc agt ccg cgt gag gcg ttg gcg atg gat ccg cag 5040 Gly PhePhe Gly Ile Ser Pro Arg Glu Ala Leu Ala Met Asp Pro Gln 1665 1670 16751680 cag cgg ttg atg ctg gag gtg tcc tgg gag gcg ttg gag cgg gcg ggc5088 Gln Arg Leu Met Leu Glu Val Ser Trp Glu Ala Leu Glu Arg Ala Gly1685 1690 1695 atc gac ccc gcc acg ttg cgc ggg tcc acg acc ggt gtc ttcgcc ggc 5136 Ile Asp Pro Ala Thr Leu Arg Gly Ser Thr Thr Gly Val Phe AlaGly 1700 1705 1710 atg tgc agt cag gac tac gcc gac ctc gtg cgc cgg gccacc gag gac 5184 Met Cys Ser Gln Asp Tyr Ala Asp Leu Val Arg Arg Ala ThrGlu Asp 1715 1720 1725 ctc gag ggc tac gcc atg acg ggc ctg tcc agc agcgtc aca tcc gga 5232 Leu Glu Gly Tyr Ala Met Thr Gly Leu Ser Ser Ser ValThr Ser Gly 1730 1735 1740 cgc gtc gcc tac acc ctg ggg ctc gag ggt ccggcg gtg acg gtg gat 5280 Arg Val Ala Tyr Thr Leu Gly Leu Glu Gly Pro AlaVal Thr Val Asp 1745 1750 1755 1760 acg gcg tgt tcg tcg tcg ttg gtg gcgctg cat ctg gcg tgt cag gcg 5328 Thr Ala Cys Ser Ser Ser Leu Val Ala LeuHis Leu Ala Cys Gln Ala 1765 1770 1775 ttg agg tcg ggg gag tgt tcg ctggcg ttg gcg ggg ggt gtg acg gtg 5376 Leu Arg Ser Gly Glu Cys Ser Leu AlaLeu Ala Gly Gly Val Thr Val 1780 1785 1790 atg tcg acg ccg ggt gcg tttgtg gag ttc tcg cgg cag cgg ggt ctg 5424 Met Ser Thr Pro Gly Ala Phe ValGlu Phe Ser Arg Gln Arg Gly Leu 1795 1800 1805 tcg ccg gac ggc cgg tgcaag gcg tac ggg tcg ggg gcc gat ggg gtc 5472 Ser Pro Asp Gly Arg Cys LysAla Tyr Gly Ser Gly Ala Asp Gly Val 1810 1815 1820 ggc tgg gcc gag ggtgtg ggt gtg ctg ttg gtg gag cgg ctg tcc gag 5520 Gly Trp Ala Glu Gly ValGly Val Leu Leu Val Glu Arg Leu Ser Glu 1825 1830 1835 1840 gct gaa cgtcgt ggt cat cgg gtt ttg gcg gtg gtg cgg ggg agt gcg 5568 Ala Glu Arg ArgGly His Arg Val Leu Ala Val Val Arg Gly Ser Ala 1845 1850 1855 gtg aatcag gac ggt gcg tcg aat ggg ttg acg gcg ccg aat ggt ccg 5616 Val Asn GlnAsp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro 1860 1865 1870 tcgcag cag cgg gtg att cgg cag gcg ttg gcg tgt gcg ggg ttg tcc 5664 Ser GlnGln Arg Val Ile Arg Gln Ala Leu Ala Cys Ala Gly Leu Ser 1875 1880 1885gtg gcg gat gtg gat gtg gtg gag ggg cac ggg acg ggt acg acg ttg 5712 ValAla Asp Val Asp Val Val Glu Gly His Gly Thr Gly Thr Thr Leu 1890 18951900 ggt gat ccg atc gag gcg cag gcg ttg ctc gcc act tat ggg cag ggt5760 Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Gly1905 1910 1915 1920 cgt tcg ggg gag cgg ccg gtg tgg ttg ggg tcg gtg aagtcg aac atc 5808 Arg Ser Gly Glu Arg Pro Val Trp Leu Gly Ser Val Lys SerAsn Ile 1925 1930 1935 ggg cat gcg cag gct gct gcg ggt gtg gcg ggt gtgatc aag atg gtg 5856 Gly His Ala Gln Ala Ala Ala Gly Val Ala Gly Val IleLys Met Val 1940 1945 1950 atg gcg ttg cgg gcg ggg gtg ttg ccg cgg acgttg cat gtg gat gag 5904 Met Ala Leu Arg Ala Gly Val Leu Pro Arg Thr LeuHis Val Asp Glu 1955 1960 1965 ccg tcg tcg cag gtg gat tgg tcg agt gggtcg gtt cgt gtg ttg gcg 5952 Pro Ser Ser Gln Val Asp Trp Ser Ser Gly SerVal Arg Val Leu Ala 1970 1975 1980 gat gag gtg gag tgg ccg ggg gtg gagggt cgg ctg cgg cgt gcg ggg 6000 Asp Glu Val Glu Trp Pro Gly Val Glu GlyArg Leu Arg Arg Ala Gly 1985 1990 1995 2000 gtg tct gcg ttc ggg gtg agtggg acg aat gcg cat gtg att ttg gag 6048 Val Ser Ala Phe Gly Val Ser GlyThr Asn Ala His Val Ile Leu Glu 2005 2010 2015 gag gcg tcc ggg ggc gcggat ggg ggt gcg ggc cgg ctg cag gag ttg 6096 Glu Ala Ser Gly Gly Ala AspGly Gly Ala Gly Arg Leu Gln Glu Leu 2020 2025 2030 ggt ccg ggg gtg gtgtcg ggt tcg ggg gtg gtg ccg tgg gtg gtg tcg 6144 Gly Pro Gly Val Val SerGly Ser Gly Val Val Pro Trp Val Val Ser 2035 2040 2045 gcg cgg tcg gagttg gcg ttg cgg ggg cag gcg cgt cgg ttg cgt ggg 6192 Ala Arg Ser Glu LeuAla Leu Arg Gly Gln Ala Arg Arg Leu Arg Gly 2050 2055 2060 gtt gtg gcggtt ggt ggg ggt gcg gat ggt gtg ggg gtg agt ccg gct 6240 Val Val Ala ValGly Gly Gly Ala Asp Gly Val Gly Val Ser Pro Ala 2065 2070 2075 2080 ggggtc ggg cgg gct ttg gtg tcg gag cgg tcg gtg ttc gag cat cgt 6288 Gly ValGly Arg Ala Leu Val Ser Glu Arg Ser Val Phe Glu His Arg 2085 2090 2095gcg gtg gtc gtg gcc gag gac cgc gac gag ttc ctg cac gca ctc gac 6336 AlaVal Val Val Ala Glu Asp Arg Asp Glu Phe Leu His Ala Leu Asp 2100 21052110 gca ctg gcc gag ggg gca ccc acc gcg ggg gtg gta cag ggt gtg gcc6384 Ala Leu Ala Glu Gly Ala Pro Thr Ala Gly Val Val Gln Gly Val Ala2115 2120 2125 gga ccg gcg gcc gac gga aag atc gcc atg ctg ttc gga ggacag ggc 6432 Gly Pro Ala Ala Asp Gly Lys Ile Ala Met Leu Phe Gly Gly GlnGly 2130 2135 2140 acc cac tgg gaa ggc atg gcg cag gaa ctc ctc ggc tcctca ccg gtc 6480 Thr His Trp Glu Gly Met Ala Gln Glu Leu Leu Gly Ser SerPro Val 2145 2150 2155 2160 ttc gcc cag cag atg tcc gac tgc gcc caa gccctc gaa ccg tac ctg 6528 Phe Ala Gln Gln Met Ser Asp Cys Ala Gln Ala LeuGlu Pro Tyr Leu 2165 2170 2175 gac tgg tct ctc ctc gac gtc ctg cgc ggcgca ccg gac gca ccc cct 6576 Asp Trp Ser Leu Leu Asp Val Leu Arg Gly AlaPro Asp Ala Pro Pro 2180 2185 2190 ctg caa cgc gtc gat gtc gtc cag cccgtc ctc ttc gcg gtg atg gtc 6624 Leu Gln Arg Val Asp Val Val Gln Pro ValLeu Phe Ala Val Met Val 2195 2200 2205 tcg ctg gcg gcg ctc tgg cgc tcgtac ggt gta cac ccg gac gcg gtg 6672 Ser Leu Ala Ala Leu Trp Arg Ser TyrGly Val His Pro Asp Ala Val 2210 2215 2220 gcc ggg cac tcg cag ggc gagatc gca gcg gcc tac gtc gcc ggt gca 6720 Ala Gly His Ser Gln Gly Glu IleAla Ala Ala Tyr Val Ala Gly Ala 2225 2230 2235 2240 ctc tcc ctc gac gacgcc gcc cgg gtc acc gcc ctg cgc agc cag gcg 6768 Leu Ser Leu Asp Asp AlaAla Arg Val Thr Ala Leu Arg Ser Gln Ala 2245 2250 2255 ctg gcc gca ctggcc ggg cag ggg gcg atg gca tcg gtc ggt ctg ccg 6816 Leu Ala Ala Leu AlaGly Gln Gly Ala Met Ala Ser Val Gly Leu Pro 2260 2265 2270 gtc gag aagctg gag ccg cgt ctt gcg aca tgg ggc gac cgt ctg gtc 6864 Val Glu Lys LeuGlu Pro Arg Leu Ala Thr Trp Gly Asp Arg Leu Val 2275 2280 2285 atc gccgcc gtg aac ggg gcg cgt tcg gcc gtg gtc tcc ggg gag ccg 6912 Ile Ala AlaVal Asn Gly Ala Arg Ser Ala Val Val Ser Gly Glu Pro 2290 2295 2300 gaagcg gtc gac gcc ctg gtg gag gag ctg tca cac gaa gac gta ccg 6960 Glu AlaVal Asp Ala Leu Val Glu Glu Leu Ser His Glu Asp Val Pro 2305 2310 23152320 gcc cgc agg ctc atg gtc gac tgg gcg tcg cac tcc ccg cag gtc gag7008 Ala Arg Arg Leu Met Val Asp Trp Ala Ser His Ser Pro Gln Val Glu2325 2330 2335 gcg atc cag ggg cgg ctg ctc gaa ctc ctc gcc ccc atc cgcgcg agg 7056 Ala Ile Gln Gly Arg Leu Leu Glu Leu Leu Ala Pro Ile Arg AlaArg 2340 2345 2350 acc ggc gac gtg ccc ttc tac tcc acc gtc acc ggc gaacgc atc gac 7104 Thr Gly Asp Val Pro Phe Tyr Ser Thr Val Thr Gly Glu ArgIle Asp 2355 2360 2365 ggc acc gaa ctc gac gcc gac tac tgg tac cgc aacctg cgc cag gtc 7152 Gly Thr Glu Leu Asp Ala Asp Tyr Trp Tyr Arg Asn LeuArg Gln Val 2370 2375 2380 gtc cgc ttc cgg gac gcg aca cag gcg ctg gtccgc gcc ggc cac acc 7200 Val Arg Phe Arg Asp Ala Thr Gln Ala Leu Val ArgAla Gly His Thr 2385 2390 2395 2400 gtc ttc atc gag gcg tgc ccg cat ccggcc gtc gcg gtc ggt gtg cag 7248 Val Phe Ile Glu Ala Cys Pro His Pro AlaVal Ala Val Gly Val Gln 2405 2410 2415 gaa acc ctg gac gag atg ggt gacttg gac agc ctg gtc gtc gga tct 7296 Glu Thr Leu Asp Glu Met Gly Asp LeuAsp Ser Leu Val Val Gly Ser 2420 2425 2430 ctg cgc cgg ggc gaa ggc ggcttg cga cgc ttc ctg atg tcc gtg gcc 7344 Leu Arg Arg Gly Glu Gly Gly LeuArg Arg Phe Leu Met Ser Val Ala 2435 2440 2445 gag ttg ttc gtg ggt ggggtg gcg gtt gag tgg tcc ggt gtg ttc ggg 7392 Glu Leu Phe Val Gly Gly ValAla Val Glu Trp Ser Gly Val Phe Gly 2450 2455 2460 agt gtt ggt cgc ggggtc gct ggt ggt tgc ggg gtg gag ctg ccg acg 7440 Ser Val Gly Arg Gly ValAla Gly Gly Cys Gly Val Glu Leu Pro Thr 2465 2470 2475 2480 tat gcg ttcgag cga gag cgc ttt tgg ctg gat gtg gag ggg gcg ccg 7488 Tyr Ala Phe GluArg Glu Arg Phe Trp Leu Asp Val Glu Gly Ala Pro 2485 2490 2495 cgg ggttcc ggg gtc tct ggg cag tgg ggt ggt cag ttg tcg gag gcg 7536 Arg Gly SerGly Val Ser Gly Gln Trp Gly Gly Gln Leu Ser Glu Ala 2500 2505 2510 gtggac acc gtg cgc ggc ggc atg ctg cgc gac tgc ctc gcc gga ctc 7584 Val AspThr Val Arg Gly Gly Met Leu Arg Asp Cys Leu Ala Gly Leu 2515 2520 2525gac ccc gcc gca cag gcc gag acc gtg ctg gac ctg gtc ctt acc cat 7632 AspPro Ala Ala Gln Ala Glu Thr Val Leu Asp Leu Val Leu Thr His 2530 25352540 gcc gcg gcc gtc ctt gga cac ggc acc gcc gat gcg gtg gtg ccc gag7680 Ala Ala Ala Val Leu Gly His Gly Thr Ala Asp Ala Val Val Pro Glu2545 2550 2555 2560 cgc gcc ttc cgc gac ctc ggt ttc gac tcc ctc acc gccgtc gaa cta 7728 Arg Ala Phe Arg Asp Leu Gly Phe Asp Ser Leu Thr Ala ValGlu Leu 2565 2570 2575 cgc aac cgc ctc aac acc gcc acg ggc ctg cgc ttcccg agg acc ctg 7776 Arg Asn Arg Leu Asn Thr Ala Thr Gly Leu Arg Phe ProArg Thr Leu 2580 2585 2590 gtg ttc gac cat ccc cgc ccg gtg gca ctc gcggca cac atc cac gag 7824 Val Phe Asp His Pro Arg Pro Val Ala Leu Ala AlaHis Ile His Glu 2595 2600 2605 cag ctg agc ggc gga agc ccg acc acc ggcact gcc ctt gcc ctt gcc 7872 Gln Leu Ser Gly Gly Ser Pro Thr Thr Gly ThrAla Leu Ala Leu Ala 2610 2615 2620 ctt cgg gcc ccg gca ccg cgt gtg gatgtc gac gag ccg att gcc att 7920 Leu Arg Ala Pro Ala Pro Arg Val Asp ValAsp Glu Pro Ile Ala Ile 2625 2630 2635 2640 gtg ggg atg gcg tgc cgt tttccg ggg ggt gtg gag tcg gcg gag gat 7968 Val Gly Met Ala Cys Arg Phe ProGly Gly Val Glu Ser Ala Glu Asp 2645 2650 2655 ttc tgg gag ttg atc gcgtcg ggt cgg gat gcg gtg ggg gag ttt ccg 8016 Phe Trp Glu Leu Ile Ala SerGly Arg Asp Ala Val Gly Glu Phe Pro 2660 2665 2670 gtc gac cgg ggt tgggac gtg gag gct ttc tat gat ccg gag ccg ggg 8064 Val Asp Arg Gly Trp AspVal Glu Ala Phe Tyr Asp Pro Glu Pro Gly 2675 2680 2685 cgg gcg ggt acgtcc tac acg cgg tgt ggt ggg ttt ttg cag ggt gcg 8112 Arg Ala Gly Thr SerTyr Thr Arg Cys Gly Gly Phe Leu Gln Gly Ala 2690 2695 2700 gcg gag ttcgat gcg ggg ttt ttc ggg atc agt ccg cgt gag gcg ttg 8160 Ala Glu Phe AspAla Gly Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu 2705 2710 2715 2720 gcgatg gat ccg cag cag cgg ttg atg ctg gag gtg tcc tgg gag gcg 8208 Ala MetAsp Pro Gln Gln Arg Leu Met Leu Glu Val Ser Trp Glu Ala 2725 2730 2735ttg gag cgg gcg ggc atc gac ccc gcc acg ctg cac ggg tcc acg acc 8256 LeuGlu Arg Ala Gly Ile Asp Pro Ala Thr Leu His Gly Ser Thr Thr 2740 27452750 ggt gtc ttc gcc ggc gtc tcg cag cag gac tac gcc gag ctc ctg cgc8304 Gly Val Phe Ala Gly Val Ser Gln Gln Asp Tyr Ala Glu Leu Leu Arg2755 2760 2765 cgc ggc acc cag gac cac gag ggg tac gcg ctc acc ggc gtctcc aac 8352 Arg Gly Thr Gln Asp His Glu Gly Tyr Ala Leu Thr Gly Val SerAsn 2770 2775 2780 agc gtc gtc tcc ggg cgg ctt tcc tac acc ttc ggc ttcgag ggt ccg 8400 Ser Val Val Ser Gly Arg Leu Ser Tyr Thr Phe Gly Phe GluGly Pro 2785 2790 2795 2800 gcg gtg acg gtg gat acg gcg tgt tcg tcg tcgttg gtg gcg ctg cat 8448 Ala Val Thr Val Asp Thr Ala Cys Ser Ser Ser LeuVal Ala Leu His 2805 2810 2815 ctg gcg tgt cag gcg ttg agg tcg ggg gagtgt tcg ctg gcg ttg gcg 8496 Leu Ala Cys Gln Ala Leu Arg Ser Gly Glu CysSer Leu Ala Leu Ala 2820 2825 2830 ggg ggt gtg acg gtg atg tcg acg ccgggt gcg ttt gtg gag ttc tcg 8544 Gly Gly Val Thr Val Met Ser Thr Pro GlyAla Phe Val Glu Phe Ser 2835 2840 2845 cgg cag cgg ggt ctg tcg ccg gacggc cgg tgc aag gcg tac ggg tcg 8592 Arg Gln Arg Gly Leu Ser Pro Asp GlyArg Cys Lys Ala Tyr Gly Ser 2850 2855 2860 ggg gcc gat ggg gtc ggc tgggcc gag ggt gtg ggt gtg ctg ttg gtg 8640 Gly Ala Asp Gly Val Gly Trp AlaGlu Gly Val Gly Val Leu Leu Val 2865 2870 2875 2880 gag cgg ctg tcc gaggct gaa cgt cgt ggt cat cgg gtt ttg gcg gtg 8688 Glu Arg Leu Ser Glu AlaGlu Arg Arg Gly His Arg Val Leu Ala Val 2885 2890 2895 gtg cgg ggg agtgcg gtg aat cag gac ggt gcg tcg aat ggg ttg acg 8736 Val Arg Gly Ser AlaVal Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr 2900 2905 2910 gcg ccg aatggt ccg tcg cag cag cgg gtg att cgg cag gcg ttg gcg 8784 Ala Pro Asn GlyPro Ser Gln Gln Arg Val Ile Arg Gln Ala Leu Ala 2915 2920 2925 tgt gcgggg ttg tcc gtg gcg gat gtg gat gtg gtg gag ggg cac ggg 8832 Cys Ala GlyLeu Ser Val Ala Asp Val Asp Val Val Glu Gly His Gly 2930 2935 2940 acgggt acg acg ttg ggt gat ccg atc gag gcg cag gcg ttg ctc gcc 8880 Thr GlyThr Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala 2945 2950 29552960 acg tac ggg cag ggt cgt tcg ggg gag cgg ccg gtg tgg ttg ggg tcg8928 Thr Tyr Gly Gln Gly Arg Ser Gly Glu Arg Pro Val Trp Leu Gly Ser2965 2970 2975 gtg aag tcg aac atc ggg cat gcg cag gct gcc gcg ggt gtggcc ggt 8976 Val Lys Ser Asn Ile Gly His Ala Gln Ala Ala Ala Gly Val AlaGly 2980 2985 2990 gtg atc aag atg gtc atg gcc ctg aac cac gaa ctg ttgccg acc agc 9024 Val Ile Lys Met Val Met Ala Leu Asn His Glu Leu Leu ProThr Ser 2995 3000 3005 ctg cac atc gac gaa ccc tcc ccc cac atc gac tggtcg agc ggc ggc 9072 Leu His Ile Asp Glu Pro Ser Pro His Ile Asp Trp SerSer Gly Gly 3010 3015 3020 gtc cgg ctt ctc acc gag ccc gta ccg tgg cagcag aac ggc cgg ccc 9120 Val Arg Leu Leu Thr Glu Pro Val Pro Trp Gln GlnAsn Gly Arg Pro 3025 3030 3035 3040 agg cgc gcg ggc gtc tcc gcg ttc ggagtc agc ggg acc aac gcc cac 9168 Arg Arg Ala Gly Val Ser Ala Phe Gly ValSer Gly Thr Asn Ala His 3045 3050 3055 gtc atc atc gag cag gcg ccg gtcgag gcg cac gtc atc agt gag ccg 9216 Val Ile Ile Glu Gln Ala Pro Val GluAla His Val Ile Ser Glu Pro 3060 3065 3070 gta ccg gct gag gcg cac gtcatc gtc gag cag gcg ccg gtc gag gcg 9264 Val Pro Ala Glu Ala His Val IleVal Glu Gln Ala Pro Val Glu Ala 3075 3080 3085 ccc cac gtg gtc gac gccacc gga ccg gcg gac ctc acc gag ccg caa 9312 Pro His Val Val Asp Ala ThrGly Pro Ala Asp Leu Thr Glu Pro Gln 3090 3095 3100 gag gag gcg gct gaaccg gag tgc gtc gct gac gcc gtg acc gag atg 9360 Glu Glu Ala Ala Glu ProGlu Cys Val Ala Asp Ala Val Thr Glu Met 3105 3110 3115 3120 tcg gct gaaccg gag tgc gtc gcc gac gcc atg tcc gag atg tcg gct 9408 Ser Ala Glu ProGlu Cys Val Ala Asp Ala Met Ser Glu Met Ser Ala 3125 3130 3135 gag tgcgtc gcc gag gcc gtg tcc gac aag tcg gct gaa ccg gag tgc 9456 Glu Cys ValAla Glu Ala Val Ser Asp Lys Ser Ala Glu Pro Glu Cys 3140 3145 3150 gtcgcc gac gcc atg tcc gac aag ccg gcc ctc ctg ccc atc ccg tgg 9504 Val AlaAsp Ala Met Ser Asp Lys Pro Ala Leu Leu Pro Ile Pro Trp 3155 3160 3165ctg ctc tcc gcc aag tcc gag cga gcg ctg cgg ggc cag gcg cga cgg 9552 LeuLeu Ser Ala Lys Ser Glu Arg Ala Leu Arg Gly Gln Ala Arg Arg 3170 31753180 ttg cgg cag ttc gct gcc agg gca tcc gat gcc cgg ccg gcc gac gtg9600 Leu Arg Gln Phe Ala Ala Arg Ala Ser Asp Ala Arg Pro Ala Asp Val3185 3190 3195 3200 gcg cac gcc ctg gcg gca cag cgg tcc gtg ttc gat caccgg gcc gtc 9648 Ala His Ala Leu Ala Ala Gln Arg Ser Val Phe Asp His ArgAla Val 3205 3210 3215 gtc gtg gcc gag gac cgc gac ggc ttc ctt cag gccctc gac gcg ctg 9696 Val Val Ala Glu Asp Arg Asp Gly Phe Leu Gln Ala LeuAsp Ala Leu 3220 3225 3230 gcc gag ggc cgg tcg gcg gac ggc ctg atc gaaggg tcg gtc ggc ccg 9744 Ala Glu Gly Arg Ser Ala Asp Gly Leu Ile Glu GlySer Val Gly Pro 3235 3240 3245 cgt ggc ggc cac tca ggc cgc cgg cgc ggaaag acc gcc atg ctg ttc 9792 Arg Gly Gly His Ser Gly Arg Arg Arg Gly LysThr Ala Met Leu Phe 3250 3255 3260 gcc gga cag ggc acg caa cgc gtg ggaatg ggc cgt cag ctg tat gcg 9840 Ala Gly Gln Gly Thr Gln Arg Val Gly MetGly Arg Gln Leu Tyr Ala 3265 3270 3275 3280 gct cac ccg gcc tac gcg gacgcg ctg gac cag gta ctg gcg gaa ctg 9888 Ala His Pro Ala Tyr Ala Asp AlaLeu Asp Gln Val Leu Ala Glu Leu 3285 3290 3295 gac ggt cac ctg gac cagccc ctg cgc ccg ctg atc cac gcc agt gcg 9936 Asp Gly His Leu Asp Gln ProLeu Arg Pro Leu Ile His Ala Ser Ala 3300 3305 3310 gat ctt gcg gat gtcgcg gat gcc gcg gat gtt ctg gac cgt acg cgg 9984 Asp Leu Ala Asp Val AlaAsp Ala Ala Asp Val Leu Asp Arg Thr Arg 3315 3320 3325 tac gcc cag ccggcg ctg ttc gcc gtc cag gtc gcg ctc ttc cgg cac 10032 Tyr Ala Gln ProAla Leu Phe Ala Val Gln Val Ala Leu Phe Arg His 3330 3335 3340 ctg gaacgt ctc ggc gtg cgc gcg gac ttc gtg gcc ggg cac tcg atc 10080 Leu GluArg Leu Gly Val Arg Ala Asp Phe Val Ala Gly His Ser Ile 3345 3350 33553360 ggc gag ctc gcg gcc gcc cac gtc gcc ggg gtg ctt ccc ctg gca gca10128 Gly Glu Leu Ala Ala Ala His Val Ala Gly Val Leu Pro Leu Ala Ala3365 3370 3375 gcc tgc cgc ctg gtg gcg gcc cgc ggg cgc ctg atg gag cagctc gca 10176 Ala Cys Arg Leu Val Ala Ala Arg Gly Arg Leu Met Glu GlnLeu Ala 3380 3385 3390 cca ggc ggc gcc atg gtc gcc gta cgg gcg agc gaagcc gag gcg cga 10224 Pro Gly Gly Ala Met Val Ala Val Arg Ala Ser GluAla Glu Ala Arg 3395 3400 3405 cag gcg ctc gac ggc cgg gaa gcc cgg gtgtcg gtc gcg gcc gtg aac 10272 Gln Ala Leu Asp Gly Arg Glu Ala Arg ValSer Val Ala Ala Val Asn 3410 3415 3420 gga ccc gcc tcg gtg gtg ttc tccggc gcc gag gac gag gtg ggg aac 10320 Gly Pro Ala Ser Val Val Phe SerGly Ala Glu Asp Glu Val Gly Asn 3425 3430 3435 3440 atg gcg gac tgg ttcgcc gag cgc ggg cgg aga gtc aag cgc ctg cga 10368 Met Ala Asp Trp PheAla Glu Arg Gly Arg Arg Val Lys Arg Leu Arg 3445 3450 3455 acc ggg catgcc ttc cac tca ccg ctg atg gac ccg atg ctg gag gag 10416 Thr Gly HisAla Phe His Ser Pro Leu Met Asp Pro Met Leu Glu Glu 3460 3465 3470 ttccag cag gtc gcg gcc tcg ctg acc tac agc gaa cca gcc att ccc 10464 PheGln Gln Val Ala Ala Ser Leu Thr Tyr Ser Glu Pro Ala Ile Pro 3475 34803485 atg gtg tcg acg ctc acc ggc gac atc gtg gcg gcg gga gaa ctg agc10512 Met Val Ser Thr Leu Thr Gly Asp Ile Val Ala Ala Gly Glu Leu Ser3490 3495 3500 gac ccc gag tac tgg gtc cgg cag gta cgg cgg acc gtg cgcttc ggc 10560 Asp Pro Glu Tyr Trp Val Arg Gln Val Arg Arg Thr Val ArgPhe Gly 3505 3510 3515 3520 gac gcg atc agc cgc ctg cac acc gac gga gtccgc acc ttc atg gaa 10608 Asp Ala Ile Ser Arg Leu His Thr Asp Gly ValArg Thr Phe Met Glu 3525 3530 3535 ctg ggc cca gac ggg acc ctg tcg gcactg gcc gag gaa tgc cta gag 10656 Leu Gly Pro Asp Gly Thr Leu Ser AlaLeu Ala Glu Glu Cys Leu Glu 3540 3545 3550 gcc acc gcc gac agc cac cccgcc gac gac gac acc ggc acc ccg caa 10704 Ala Thr Ala Asp Ser His ProAla Asp Asp Asp Thr Gly Thr Pro Gln 3555 3560 3565 gag aac ctg ctc atcccg ctc cta cgg ccg gac agc ccg gaa ccc ggc 10752 Glu Asn Leu Leu IlePro Leu Leu Arg Pro Asp Ser Pro Glu Pro Gly 3570 3575 3580 acc ctg ctcacc ggc ttg gcc cgg ctg cat acg cac gga gcg gcg gcg 10800 Thr Leu LeuThr Gly Leu Ala Arg Leu His Thr His Gly Ala Ala Ala 3585 3590 3595 3600gtc aac tgg ccc gcc gcc ctg ccc gaa cgc gat cga gcc cgc cac ctc 10848Val Asn Trp Pro Ala Ala Leu Pro Glu Arg Asp Arg Ala Arg His Leu 36053610 3615 gac ctg ccg acc tac gcc ttc gat cac cac cgc tac tgg gtc gacacc 10896 Asp Leu Pro Thr Tyr Ala Phe Asp His His Arg Tyr Trp Val AspThr 3620 3625 3630 tcg gcc ggc cac ccg ggg gac ctg tcg gca gcg ggg ctcggc acc gcc 10944 Ser Ala Gly His Pro Gly Asp Leu Ser Ala Ala Gly LeuGly Thr Ala 3635 3640 3645 ggg cat ccc ctg ctc ggt tcc gcg gtg gca ctggcc gag tcg cag gaa 10992 Gly His Pro Leu Leu Gly Ser Ala Val Ala LeuAla Glu Ser Gln Glu 3650 3655 3660 ctc ctc ttc acc ggc cgt ctc tcc ctgcgc aca cac ccg tgg ctg gcc 11040 Leu Leu Phe Thr Gly Arg Leu Ser LeuArg Thr His Pro Trp Leu Ala 3665 3670 3675 3680 gac cac gcc atc ttc ggtacc gtc ctg ctg ccc ggc acg gcc atc ctg 11088 Asp His Ala Ile Phe GlyThr Val Leu Leu Pro Gly Thr Ala Ile Leu 3685 3690 3695 gaa ctg gcc gtgcgc gca ggc gac gag gtc gac tgc ggc acc gtc gag 11136 Glu Leu Ala ValArg Ala Gly Asp Glu Val Asp Cys Gly Thr Val Glu 3700 3705 3710 gaa ctcacc ctg cgg aca ccg ctc gtc ctt ccc gaa cag ggc tcg gtg 11184 Glu LeuThr Leu Arg Thr Pro Leu Val Leu Pro Glu Gln Gly Ser Val 3715 3720 3725atc ctg caa ctc tcc gtc ggg gca ccc cag ggc ccc cag acg ccc gag 11232Ile Leu Gln Leu Ser Val Gly Ala Pro Gln Gly Pro Gln Thr Pro Glu 37303735 3740 gag ccc gaa cgg cgc acc ttc gcc ctg tac gcc cgc gaa gac gacgga 11280 Glu Pro Glu Arg Arg Thr Phe Ala Leu Tyr Ala Arg Glu Asp AspGly 3745 3750 3755 3760 ctg tcg tcc tcg tcc gcg gcg gcg acc ggc acc gagtgg acc tgc cac 11328 Leu Ser Ser Ser Ser Ala Ala Ala Thr Gly Thr GluTrp Thr Cys His 3765 3770 3775 gcc acc ggc gtc ctg acc ggc acc gcc cggccc gcg gag gag cac aca 11376 Ala Thr Gly Val Leu Thr Gly Thr Ala ArgPro Ala Glu Glu His Thr 3780 3785 3790 cag gaa ccg tgg ccg ccc gcc gacgca gca ccg gtg gac ctg gac ggc 11424 Gln Glu Pro Trp Pro Pro Ala AspAla Ala Pro Val Asp Leu Asp Gly 3795 3800 3805 tgg tac gag cag ctg gccggc gcc ggc ctg gga tac ggg ccg gtg ttc 11472 Trp Tyr Glu Gln Leu AlaGly Ala Gly Leu Gly Tyr Gly Pro Val Phe 3810 3815 3820 cag ggg ctg cgcgag gtc tgg cgg cgc ggg gac gag gtg ttc gcc gtc 11520 Gln Gly Leu ArgGlu Val Trp Arg Arg Gly Asp Glu Val Phe Ala Val 3825 3830 3835 3840 gtcacc ctg ccc gag agc acg gag gga cag gcg gcc gac gcc gcc cgg 11568 ValThr Leu Pro Glu Ser Thr Glu Gly Gln Ala Ala Asp Ala Ala Arg 3845 38503855 tac gcc ctg cac ccg gcc ctg ctg gac gcg gca ctg cac ccg gtc gtt11616 Tyr Ala Leu His Pro Ala Leu Leu Asp Ala Ala Leu His Pro Val Val3860 3865 3870 ctg cgc cac gag ggc gat gcc gcc gcc gac gga cac ggc tggctg ccg 11664 Leu Arg His Glu Gly Asp Ala Ala Ala Asp Gly His Gly TrpLeu Pro 3875 3880 3885 ttc tcc tgg acc ggc gtc acg gtc gcc gcc tcc ggcgcc tcc acc ctg 11712 Phe Ser Trp Thr Gly Val Thr Val Ala Ala Ser GlyAla Ser Thr Leu 3890 3895 3900 cac gtc cgt ctc acc gtc cgc acg gac gaggac gcg gtc gga ctg ctg 11760 His Val Arg Leu Thr Val Arg Thr Asp GluAsp Ala Val Gly Leu Leu 3905 3910 3915 3920 gcc acc gac gca tcg gga cgcatc gtc atc tcc gcg ggg tcc ctc gcc 11808 Ala Thr Asp Ala Ser Gly ArgIle Val Ile Ser Ala Gly Ser Leu Ala 3925 3930 3935 ttc cgg ccc gtc tccgcc gag cag ctc cag gcc gcg cgc acc ggc tac 11856 Phe Arg Pro Val SerAla Glu Gln Leu Gln Ala Ala Arg Thr Gly Tyr 3940 3945 3950 cac gac cacctc ttc cgc atc gaa tgg cgg ccg ctg cac ctc ccc acc 11904 His Asp HisLeu Phe Arg Ile Glu Trp Arg Pro Leu His Leu Pro Thr 3955 3960 3965 acaccg gca cgg aca gcc gac tgg gcc cta atc ggc ccc ggt gcc cgg 11952 ThrPro Ala Arg Thr Ala Asp Trp Ala Leu Ile Gly Pro Gly Ala Arg 3970 39753980 cgg acg gcc gcc gtc ctg gag cgc aac ggc gcc tcc tgg cag gcc tac12000 Arg Thr Ala Ala Val Leu Glu Arg Asn Gly Ala Ser Trp Gln Ala Tyr3985 3990 3995 4000 ccg gac ccg gcg gct ctc gca gaa gcc ctg gcg gcc ggcgcc ccg gca 12048 Pro Asp Pro Ala Ala Leu Ala Glu Ala Leu Ala Ala GlyAla Pro Ala 4005 4010 4015 ccg ggc atg gtc gtc atc tcg tgc gag ccg gacggc gca tcc gcc ccc 12096 Pro Gly Met Val Val Ile Ser Cys Glu Pro AspGly Ala Ser Ala Pro 4020 4025 4030 acc gat tcc gcc ctc acc gat tcc gccctc acc gat tcc gcc ccg gcc 12144 Thr Asp Ser Ala Leu Thr Asp Ser AlaLeu Thr Asp Ser Ala Pro Ala 4035 4040 4045 ggc tcg gcc ccg gcc gac tccacc gcc ctc gcc gac gcc acc cgg caa 12192 Gly Ser Ala Pro Ala Asp SerThr Ala Leu Ala Asp Ala Thr Arg Gln 4050 4055 4060 gcc acc acc cgc gtcctc gcc ctg ctc cag gaa tgg gtc gcc gac gaa 12240 Ala Thr Thr Arg ValLeu Ala Leu Leu Gln Glu Trp Val Ala Asp Glu 4065 4070 4075 4080 cgg ctcgcg gcc tgc cgc ctg gcc ctc ctc acg cac ggc tcg gtc acc 12288 Arg LeuAla Ala Cys Arg Leu Ala Leu Leu Thr His Gly Ser Val Thr 4085 4090 4095gcg acc ccc gac gag ccc gtg tcc gac ctc gca cac gcc gcc gtc tgg 12336Ala Thr Pro Asp Glu Pro Val Ser Asp Leu Ala His Ala Ala Val Trp 41004105 4110 gga ctg gtc cgc tcc gtg cag acc gag aac ccc gac cgg ttc ctgctg 12384 Gly Leu Val Arg Ser Val Gln Thr Glu Asn Pro Asp Arg Phe LeuLeu 4115 4120 4125 gcc gac acc gac gac acc gac gcc tcc cgc aac gcc cttccc ctg ctg 12432 Ala Asp Thr Asp Asp Thr Asp Ala Ser Arg Asn Ala LeuPro Leu Leu 4130 4135 4140 gcc ggg gaa ccg cag atc gcc ctg cga aat ggtgcc gtc cgc atc ccg 12480 Ala Gly Glu Pro Gln Ile Ala Leu Arg Asn GlyAla Val Arg Ile Pro 4145 4150 4155 4160 cgg atg aca cga gtg ccc gtc cggcag cca cag ccg agc acc acc gac 12528 Arg Met Thr Arg Val Pro Val ArgGln Pro Gln Pro Ser Thr Thr Asp 4165 4170 4175 gcc gac tgg gac ccg gaggcc acg gtc ctc atc acg ggc ggt acc ggc 12576 Ala Asp Trp Asp Pro GluAla Thr Val Leu Ile Thr Gly Gly Thr Gly 4180 4185 4190 gtc ctc ggc cggctc gtc gcc cgt cat ctc gcc acg gcc cac ggg gta 12624 Val Leu Gly ArgLeu Val Ala Arg His Leu Ala Thr Ala His Gly Val 4195 4200 4205 cgg cacctg ctg ctg gcc acc cgc cgc ggc acg gcc gcg gac ggc gcc 12672 Arg HisLeu Leu Leu Ala Thr Arg Arg Gly Thr Ala Ala Asp Gly Ala 4210 4215 4220gcc gac ctg gtc gcc gaa ctc gcc ggc ctc ggc gcc gag gcc acg gtc 12720Ala Asp Leu Val Ala Glu Leu Ala Gly Leu Gly Ala Glu Ala Thr Val 42254230 4235 4240 gcg gcc tgc gac atc ggg gac cgg gcg gcc gtc gcc gcg ctcctc gac 12768 Ala Ala Cys Asp Ile Gly Asp Arg Ala Ala Val Ala Ala LeuLeu Asp 4245 4250 4255 caa gtg ccc gcg cag cac ccc ctg aaa gcc gtg atccac acg gcc ggt 12816 Gln Val Pro Ala Gln His Pro Leu Lys Ala Val IleHis Thr Ala Gly 4260 4265 4270 gtg gtc gac gac ggc atc ctc acc tcg ctcact ccg gag cgc atg gag 12864 Val Val Asp Asp Gly Ile Leu Thr Ser LeuThr Pro Glu Arg Met Glu 4275 4280 4285 gcc gtc ctg cac gcg aag gcg ttcggc gcc gcg cac ctg cac gac ctg 12912 Ala Val Leu His Ala Lys Ala PheGly Ala Ala His Leu His Asp Leu 4290 4295 4300 acc cgc gac gcc ggc ctcacc acc ttc acc gtc ttc tcc tcg gcc gcc 12960 Thr Arg Asp Ala Gly LeuThr Thr Phe Thr Val Phe Ser Ser Ala Ala 4305 4310 4315 4320 gcc tcc ttcggc agt ccc gga cag ggc aac tac acc gcg gcg aac gcc 13008 Ala Ser PheGly Ser Pro Gly Gln Gly Asn Tyr Thr Ala Ala Asn Ala 4325 4330 4335 tttctg gac gcc ctg atg cag cac cgc cac acc cag gca ctg ccg ggc 13056 PheLeu Asp Ala Leu Met Gln His Arg His Thr Gln Ala Leu Pro Gly 4340 43454350 cgg tcg ctc gcc tgg ggc ctt tgg ggc gag gcc gac ggc atg acc cgc13104 Arg Ser Leu Ala Trp Gly Leu Trp Gly Glu Ala Asp Gly Met Thr Arg4355 4360 4365 aac ctc gcc ggc acc gac ttc gcg cgc atg gcc cgc ggc ggcctg ctc 13152 Asn Leu Ala Gly Thr Asp Phe Ala Arg Met Ala Arg Gly GlyLeu Leu 4370 4375 4380 ccc ctg tcc aac gca cag gga ctc gcg ctc ctc gacaca gcg gat cgc 13200 Pro Leu Ser Asn Ala Gln Gly Leu Ala Leu Leu AspThr Ala Asp Arg 4385 4390 4395 4400 ctc ggc cct ttc ggt gac ggg ctg ctcctc gcc acc cgg ctc gac gcg 13248 Leu Gly Pro Phe Gly Asp Gly Leu LeuLeu Ala Thr Arg Leu Asp Ala 4405 4410 4415 gcc acc ctc cac gca cag gccacg gcc ggc gcc ctg ccg cgc atc ctg 13296 Ala Thr Leu His Ala Gln AlaThr Ala Gly Ala Leu Pro Arg Ile Leu 4420 4425 4430 cac ggg ctg atc cgcatc ccg gcc cgg cgg tcc gcc gac cac ggc atc 13344 His Gly Leu Ile ArgIle Pro Ala Arg Arg Ser Ala Asp His Gly Ile 4435 4440 4445 gcg acc gacacc ccc gcc acg ctg cgc gag cgc ctg gcc gga ctc acc 13392 Ala Thr AspThr Pro Ala Thr Leu Arg Glu Arg Leu Ala Gly Leu Thr 4450 4455 4460 atcccc gcg cag cgc acc ggt ctc ctc ctg gaa ctc gta cgg acc cat 13440 IlePro Ala Gln Arg Thr Gly Leu Leu Leu Glu Leu Val Arg Thr His 4465 44704475 4480 gcc gcc gcc gtc ctc ggc cac ccc acc agc gcc gtc aca gcc gcggac 13488 Ala Ala Ala Val Leu Gly His Pro Thr Ser Ala Val Thr Ala AlaAsp 4485 4490 4495 ggc gca ctc ccg gac gat ctg gtc ccg gcc gac acc gagttc cgc gac 13536 Gly Ala Leu Pro Asp Asp Leu Val Pro Ala Asp Thr GluPhe Arg Asp 4500 4505 4510 ctc ggc ttc gac tcg ctg acc gcc gtc gaa ctccgc aac cgg atc aac 13584 Leu Gly Phe Asp Ser Leu Thr Ala Val Glu LeuArg Asn Arg Ile Asn 4515 4520 4525 gcc gtc acc ggc ctg cgc ctc ccg gcaacg ctc atc ttc gac cag ccc 13632 Ala Val Thr Gly Leu Arg Leu Pro AlaThr Leu Ile Phe Asp Gln Pro 4530 4535 4540 agc ccc gcg gca ctc gcc gatcac ctc gcg acc cgc ctg acg gcc gag 13680 Ser Pro Ala Ala Leu Ala AspHis Leu Ala Thr Arg Leu Thr Ala Glu 4545 4550 4555 4560 gcg ggc acg ccggac gag ccg gcc cct gcc gcc gcg gca gcc ggg gcc 13728 Ala Gly Thr ProAsp Glu Pro Ala Pro Ala Ala Ala Ala Ala Gly Ala 4565 4570 4575 ggg agcgca ggg agt gcc gag acc gga cag cag cgc agt acg ggg agc 13776 Gly SerAla Gly Ser Ala Glu Thr Gly Gln Gln Arg Ser Thr Gly Ser 4580 4585 4590gag aag cag cag acc agg ggc ggc acc tcc acc gaa acc gtc gaa tcc 13824Glu Lys Gln Gln Thr Arg Gly Gly Thr Ser Thr Glu Thr Val Glu Ser 45954600 4605 ctg ttc tgg atc gga cac gac acc cgc cgc atc gag gag tcc atggcc 13872 Leu Phe Trp Ile Gly His Asp Thr Arg Arg Ile Glu Glu Ser MetAla 4610 4615 4620 ctg ctc tcg gcg gcc tcc ttc ttc cgg ccc gcc ttc acggac ccc tcg 13920 Leu Leu Ser Ala Ala Ser Phe Phe Arg Pro Ala Phe ThrAsp Pro Ser 4625 4630 4635 4640 gac atc ccg gag ccg acg ttc gtc cgg ctcgcc cag ggt gaa gcg cgc 13968 Asp Ile Pro Glu Pro Thr Phe Val Arg LeuAla Gln Gly Glu Ala Arg 4645 4650 4655 gcc caa ggt gaa gca ctc gcc cggggc gaa aca cgg ccc gcc ctc atc 14016 Ala Gln Gly Glu Ala Leu Ala ArgGly Glu Thr Arg Pro Ala Leu Ile 4660 4665 4670 tgc ctg ccc acc gtc gccgcc gtg tcg agc gtg tac cag tac tca cgt 14064 Cys Leu Pro Thr Val AlaAla Val Ser Ser Val Tyr Gln Tyr Ser Arg 4675 4680 4685 ttc gcg gcg ggactg aac gga cac cga gac gtc tgg tac gtt cct gcg 14112 Phe Ala Ala GlyLeu Asn Gly His Arg Asp Val Trp Tyr Val Pro Ala 4690 4695 4700 cca gggttc ctg gag ggc gaa ccc ctg ccg tcc gga atc ggc gcg gtg 14160 Pro GlyPhe Leu Glu Gly Glu Pro Leu Pro Ser Gly Ile Gly Ala Val 4705 4710 47154720 acc cgc atg ttc gcc gac gcg atc gtc cgg ttc acc gac ggc gcg cct14208 Thr Arg Met Phe Ala Asp Ala Ile Val Arg Phe Thr Asp Gly Ala Pro4725 4730 4735 ttt gcg ctc gcc ggg cat tcc gcg ggc gga tgg ttc gtc tacgcg gtg 14256 Phe Ala Leu Ala Gly His Ser Ala Gly Gly Trp Phe Val TyrAla Val 4740 4745 4750 acg agt cat ctg gag cgt cta ggc gtc cgt ccg gaagcg gtg gtg acc 14304 Thr Ser His Leu Glu Arg Leu Gly Val Arg Pro GluAla Val Val Thr 4755 4760 4765 atg gac gcc tat ctc ccg gac gac ggc atcgca cct gtc gcg tcc gcg 14352 Met Asp Ala Tyr Leu Pro Asp Asp Gly IleAla Pro Val Ala Ser Ala 4770 4775 4780 ctg aca agt gaa atc ttc gac cgcgtc acg cag ttt gtg gac gtg gac 14400 Leu Thr Ser Glu Ile Phe Asp ArgVal Thr Gln Phe Val Asp Val Asp 4785 4790 4795 4800 tac aca cgc ctg gtcgcc atg ggc gga tac ttc cgc atc ttc tcc ggc 14448 Tyr Thr Arg Leu ValAla Met Gly Gly Tyr Phe Arg Ile Phe Ser Gly 4805 4810 4815 tgg agt cctccg gac atc acc aca ccc gcc ctc ttc ctg cgc ggc cgg 14496 Trp Ser ProPro Asp Ile Thr Thr Pro Ala Leu Phe Leu Arg Gly Arg 4820 4825 4830 gacgga gaa cag atg ccg ccg ccg tgg gga gtt ccg cac acc gtt ctg 14544 AspGly Glu Gln Met Pro Pro Pro Trp Gly Val Pro His Thr Val Leu 4835 48404845 gac atc cag ggg aat cac ttc acg atg ctg gaa cag ttt gcg gat tcg14592 Asp Ile Gln Gly Asn His Phe Thr Met Leu Glu Gln Phe Ala Asp Ser4850 4855 4860 act gct cgg cat gtc gac gaa tgg ctg aca gaa atc gca tcagtg cgg 14640 Thr Ala Arg His Val Asp Glu Trp Leu Thr Glu Ile Ala SerVal Arg 4865 4870 4875 4880 cgc tgatcgcgcc tctgatcgcg gtcctgatcgcggccctgat cggcgggtcg 14693 Arg ggcacagccc ggtcggccgg tcggccagtcggccagtcgg tggtatccgg tcggctccgg 14753 catcgatcag tgctttcccc cttacggccatacgggcctt tctgagactt cttgaatttg 14813 ggagacagtg atg gac acg tcc agcgaa aag ctc gtc gac gcg ctt agg 14862 Met Asp Thr Ser Ser Glu Lys LeuVal Asp Ala Leu Arg 4885 4890 gcg tct ctg aag gcg aac cag acc ctg cgggca cgt aat gag caa ctg 14910 Ala Ser Leu Lys Ala Asn Gln Thr Leu ArgAla Arg Asn Glu Gln Leu 4895 4900 4905 4910 gca gcc gcc atg gag gcg tccagc gag ccg att gcg att gtg ggg atg 14958 Ala Ala Ala Met Glu Ala SerSer Glu Pro Ile Ala Ile Val Gly Met 4915 4920 4925 gcg tgt cgt ttt ccgggt ggg gtg tgt tcg ccg gag gag ttg tgg gag 15006 Ala Cys Arg Phe ProGly Gly Val Cys Ser Pro Glu Glu Leu Trp Glu 4930 4935 4940 ctg gtt gcgtcg ggt ggg gat gcg att ggt gaa ttt ccg gcc ggt cgg 15054 Leu Val AlaSer Gly Gly Asp Ala Ile Gly Glu Phe Pro Ala Gly Arg 4945 4950 4955 gggtgg gat ctg gag ggg ttg ttt gat tcg gac cct gac cgg tcg ggg 15102 GlyTrp Asp Leu Glu Gly Leu Phe Asp Ser Asp Pro Asp Arg Ser Gly 4960 49654970 acg tcg tac gcg cgg tat ggc ggg ttt ttg tat gag gcg ggg gag ttc15150 Thr Ser Tyr Ala Arg Tyr Gly Gly Phe Leu Tyr Glu Ala Gly Glu Phe4975 4980 4985 4990 gat gcg gac ttc ttc ggg atc agt ccg cgt gag gcg ttggcg atg gat 15198 Asp Ala Asp Phe Phe Gly Ile Ser Pro Arg Glu Ala LeuAla Met Asp 4995 5000 5005 ccg cag cag cgg ttg ttg ctg gag acg tcg tgggag gcg ttc gag cgg 15246 Pro Gln Gln Arg Leu Leu Leu Glu Thr Ser TrpGlu Ala Phe Glu Arg 5010 5015 5020 gcg ggt atc gat ccg ctg tcg atg cgtggc tcc cgt acg ggt gtc ttc 15294 Ala Gly Ile Asp Pro Leu Ser Met ArgGly Ser Arg Thr Gly Val Phe 5025 5030 5035 gcc ggg gtg atg tac cac gactac gga tcc cgc ctg ggt acc atc ccc 15342 Ala Gly Val Met Tyr His AspTyr Gly Ser Arg Leu Gly Thr Ile Pro 5040 5045 5050 gag gga ttc gag ggctac atc ggc aac ggt agc ggc ggc gcc gtc gcg 15390 Glu Gly Phe Glu GlyTyr Ile Gly Asn Gly Ser Gly Gly Ala Val Ala 5055 5060 5065 5070 tcg ggccgc gtc gcc tac acg ctc ggt ctc gag ggc cct gcc gtc tcg 15438 Ser GlyArg Val Ala Tyr Thr Leu Gly Leu Glu Gly Pro Ala Val Ser 5075 5080 5085gtg gac acg gca tgt tcg tcg tcg ttg gtg gcg ctg cat ctg gcg tgc 15486Val Asp Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys 50905095 5100 cag tcg ctg cgg tcg ggt gag tgc acg ctc gcg ctg gcc ggc ggtgtg 15534 Gln Ser Leu Arg Ser Gly Glu Cys Thr Leu Ala Leu Ala Gly GlyVal 5105 5110 5115 acg gtg atg tcg acc ccg cac ctc ttc gtc gag ttc tcacgc cag cgc 15582 Thr Val Met Ser Thr Pro His Leu Phe Val Glu Phe SerArg Gln Arg 5120 5125 5130 gga ctg tcg gtg gac ggc cgc tgc aag tcc ttcgcg ggt gga gcc gac 15630 Gly Leu Ser Val Asp Gly Arg Cys Lys Ser PheAla Gly Gly Ala Asp 5135 5140 5145 5150 ggc acc ggc atg ggc gag ggc gtcggg atg ctg ttg gtg gag cgg ttg 15678 Gly Thr Gly Met Gly Glu Gly ValGly Met Leu Leu Val Glu Arg Leu 5155 5160 5165 tcg gat gcg gtg cgg ctgggg cat cgg gtg ctg gcg gtg ctg cgc ggc 15726 Ser Asp Ala Val Arg LeuGly His Arg Val Leu Ala Val Leu Arg Gly 5170 5175 5180 agt gcg gtc aatcag gac ggt gcg tcg aat ggg ttg acg gcg ccg aat 15774 Ser Ala Val AsnGln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn 5185 5190 5195 ggt ccggct cag gag cgg gtg atc cgg cag gcg ttg gcg aac gcg ggg 15822 Gly ProAla Gln Glu Arg Val Ile Arg Gln Ala Leu Ala Asn Ala Gly 5200 5205 5210ttg tcc gtg gcg gat gtg gat gtg gtg gag ggg cat ggg acg ggc acg 15870Leu Ser Val Ala Asp Val Asp Val Val Glu Gly His Gly Thr Gly Thr 52155220 5225 5230 acg ctg ggt gat ccg atc gag gcg cag gcg ttg ctc gcc acgtac ggg 15918 Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala ThrTyr Gly 5235 5240 5245 cag cgg gcc ggt aac agg ccg ctg tgg ctg gga tcggtg aag tcg aac 15966 Gln Arg Ala Gly Asn Arg Pro Leu Trp Leu Gly SerVal Lys Ser Asn 5250 5255 5260 atc ggc cat gcg cag gct gcc gcg ggt gtgggt ggg gtc atc aag atg 16014 Ile Gly His Ala Gln Ala Ala Ala Gly ValGly Gly Val Ile Lys Met 5265 5270 5275 gtg atg gcg ttg cgg gag ggg gtgttg ccg cgg acg ttg cat gtg gat 16062 Val Met Ala Leu Arg Glu Gly ValLeu Pro Arg Thr Leu His Val Asp 5280 5285 5290 gag ccg tcg ccg cag gtggac tgg tcc gcg ggg gcg gtg cgg ctg ctg 16110 Glu Pro Ser Pro Gln ValAsp Trp Ser Ala Gly Ala Val Arg Leu Leu 5295 5300 5305 5310 acg gag gcggtg ccg tgg ccg ggg gac gcg gca ggg cgg ttg cgg cgg 16158 Thr Glu AlaVal Pro Trp Pro Gly Asp Ala Ala Gly Arg Leu Arg Arg 5315 5320 5325 gcggga gtg tcg tcg ttc ggg gtc agt ggc acg aat gcg cat gtg att 16206 AlaGly Val Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val Ile 5330 53355340 ttg gag gag gcg ccg gcg gcg ggg ggc tgt gtt gcc ggg ggt ggg gtg16254 Leu Glu Glu Ala Pro Ala Ala Gly Gly Cys Val Ala Gly Gly Gly Val5345 5350 5355 ttg gag ggt gct ccg ggt ctt gcc att tcg gtg gct gag tcggtg gcc 16302 Leu Glu Gly Ala Pro Gly Leu Ala Ile Ser Val Ala Glu SerVal Ala 5360 5365 5370 gct cca gtg gct gtg tct gcg ccg gtg gct gag tcggtg ccg gtg ccg 16350 Ala Pro Val Ala Val Ser Ala Pro Val Ala Glu SerVal Pro Val Pro 5375 5380 5385 5390 gtg ccg gtg ccg gtt cct gtg ccg gtgtcg gct agg tct gag gct ggg 16398 Val Pro Val Pro Val Pro Val Pro ValSer Ala Arg Ser Glu Ala Gly 5395 5400 5405 ttg cgg gcg cag gcg gag gcgttg cgt cag tac gtg gca gtc cgg ccg 16446 Leu Arg Ala Gln Ala Glu AlaLeu Arg Gln Tyr Val Ala Val Arg Pro 5410 5415 5420 gac gtt tcg ctt gccgat gtg ggt gcg ggt ctg gcc tgt ggg cgg gct 16494 Asp Val Ser Leu AlaAsp Val Gly Ala Gly Leu Ala Cys Gly Arg Ala 5425 5430 5435 gtg ctg gagcat cgt gcg gtc gtc ctg gcc gcg gac cgt gag gag ctg 16542 Val Leu GluHis Arg Ala Val Val Leu Ala Ala Asp Arg Glu Glu Leu 5440 5445 5450 gtgcaa ggg ttg ggg gcg ctg gcg gcg ggt gag ccg gat cgg cgg gtg 16590 ValGln Gly Leu Gly Ala Leu Ala Ala Gly Glu Pro Asp Arg Arg Val 5455 54605465 5470 acc acg ggt cat gcg ccg ggt ggt gac cgg ggc ggt gtc gtc ttcgtg 16638 Thr Thr Gly His Ala Pro Gly Gly Asp Arg Gly Gly Val Val PheVal 5475 5480 5485 ttt ccc gga cag ggt ggg cag tgg gcc ggg atg ggt gtgcgt ctg ctc 16686 Phe Pro Gly Gln Gly Gly Gln Trp Ala Gly Met Gly ValArg Leu Leu 5490 5495 5500 gcc tcc tct ccg gtg ttc gcc cgg cgg atg caggcg tgc gag gag gct 16734 Ala Ser Ser Pro Val Phe Ala Arg Arg Met GlnAla Cys Glu Glu Ala 5505 5510 5515 ctg gcg ccg tgg gtg gac tgg tct gtggtg gac atc ctg cgc cgg gac 16782 Leu Ala Pro Trp Val Asp Trp Ser ValVal Asp Ile Leu Arg Arg Asp 5520 5525 5530 gcg ggg gat gcg gtg tgg gagcgg gcc gat gtg gtc cag cct gtg ctg 16830 Ala Gly Asp Ala Val Trp GluArg Ala Asp Val Val Gln Pro Val Leu 5535 5540 5545 5550 ttc agc gtc atggtg tct ttg gct gct ctg tgg cgt tcc tac ggt atc 16878 Phe Ser Val MetVal Ser Leu Ala Ala Leu Trp Arg Ser Tyr Gly Ile 5555 5560 5565 gaa cccgac gcg gtc ctt ggc cat tcc cag ggc gag atc gcg gcc gcg 16926 Glu ProAsp Ala Val Leu Gly His Ser Gln Gly Glu Ile Ala Ala Ala 5570 5575 5580cat gtg tgt ggg gcg ctg agc ctg aag gac gcg gcg aag act gtt gcg 16974His Val Cys Gly Ala Leu Ser Leu Lys Asp Ala Ala Lys Thr Val Ala 55855590 5595 ctg cgc agc cgg gcg ctg gcc gct gtg cgg ggc cgg ggc ggc atggcc 17022 Leu Arg Ser Arg Ala Leu Ala Ala Val Arg Gly Arg Gly Gly MetAla 5600 5605 5610 tca gtg ccg ctg cct gcc cag gag gtg gag cag ctc attggt gag cgg 17070 Ser Val Pro Leu Pro Ala Gln Glu Val Glu Gln Leu IleGly Glu Arg 5615 5620 5625 5630 tgg gcg ggg cgg ttg tgg gtg gcg gcg gtcaac ggc ccc cgc tcc acc 17118 Trp Ala Gly Arg Leu Trp Val Ala Ala ValAsn Gly Pro Arg Ser Thr 5635 5640 5645 gcc gtc tcg ggg gat gcc gag gcggtg gac gag gtg ctg gcg tac tgt 17166 Ala Val Ser Gly Asp Ala Glu AlaVal Asp Glu Val Leu Ala Tyr Cys 5650 5655 5660 gcc ggc acc ggg gtg cgggcc cgg cgg atc ccg gtc gac tat gcc tcg 17214 Ala Gly Thr Gly Val ArgAla Arg Arg Ile Pro Val Asp Tyr Ala Ser 5665 5670 5675 cac tgc ccc catgtg cag ccc ctg cgg gag gag ttg ctg gag ctg ctg 17262 His Cys Pro HisVal Gln Pro Leu Arg Glu Glu Leu Leu Glu Leu Leu 5680 5685 5690 ggg gacatc agc ccg cag ccg tcc ggc gtg ccg ttc ttc tcc acg gtg 17310 Gly AspIle Ser Pro Gln Pro Ser Gly Val Pro Phe Phe Ser Thr Val 5695 5700 57055710 gag ggc acc tgg ctg gac acc aca acc ctg gac gcc gcc tac tgg tac17358 Glu Gly Thr Trp Leu Asp Thr Thr Thr Leu Asp Ala Ala Tyr Trp Tyr5715 5720 5725 cgc aac ctg cac cag cct gtc cgt ttc agc gat gcc gtc caggcc ctg 17406 Arg Asn Leu His Gln Pro Val Arg Phe Ser Asp Ala Val GlnAla Leu 5730 5735 5740 gcg gat gac gga cac cgc gtc ttc gtc gaa gtc agcccc cac ccc acc 17454 Ala Asp Asp Gly His Arg Val Phe Val Glu Val SerPro His Pro Thr 5745 5750 5755 ctc gtc ccc gcc atc gaa gac acc acc gaagac acc gcc gaa gac gtc 17502 Leu Val Pro Ala Ile Glu Asp Thr Thr GluAsp Thr Ala Glu Asp Val 5760 5765 5770 acc gcg atc ggc agc ctc cgc cgcggc gac aac gac acc cgc cgc ttc 17550 Thr Ala Ile Gly Ser Leu Arg ArgGly Asp Asn Asp Thr Arg Arg Phe 5775 5780 5785 5790 ctc acc gcc ctc gcccac acc cac acc acc ggc atc ggc aca ccc acc 17598 Leu Thr Ala Leu AlaHis Thr His Thr Thr Gly Ile Gly Thr Pro Thr 5795 5800 5805 acc tgg caccac cac tac acc cac cac cac acc cac ccc cac aac cac 17646 Thr Trp HisHis His Tyr Thr His His His Thr His Pro His Asn His 5810 5815 5820 cacctc gac ctc ccc act tat ccc ttc caa cgc cag cac tac tgg ctc 17694 HisLeu Asp Leu Pro Thr Tyr Pro Phe Gln Arg Gln His Tyr Trp Leu 5825 58305835 gac gct ccc acg gga gca ggt gac gtc gcc gct gct ggc ttg gag ccg17742 Asp Ala Pro Thr Gly Ala Gly Asp Val Ala Ala Ala Gly Leu Glu Pro5840 5845 5850 gcc gaa cac cct ctg ctc gcg gca aca gtc caa ctc gca gacacg gac 17790 Ala Glu His Pro Leu Leu Ala Ala Thr Val Gln Leu Ala AspThr Asp 5855 5860 5865 5870 ggc tgc cta ctg acg ggt cgc ctg tcc ttg cgctcg cat ccg tgg ctg 17838 Gly Cys Leu Leu Thr Gly Arg Leu Ser Leu ArgSer His Pro Trp Leu 5875 5880 5885 ggc gat tac gag gtg ggg ggt gcg gtcctg ctg tcg ggg tcg gcg ttc 17886 Gly Asp Tyr Glu Val Gly Gly Ala ValLeu Leu Ser Gly Ser Ala Phe 5890 5895 5900 gtg gag ctg gcg gtc cag gttggc gaa cgc gtg ggc tgc acc cga atc 17934 Val Glu Leu Ala Val Gln ValGly Glu Arg Val Gly Cys Thr Arg Ile 5905 5910 5915 gag caa ctc act gtgcat gcg ccg ctg gtg gtt cct gtg ggt ggg ggt 17982 Glu Gln Leu Thr ValHis Ala Pro Leu Val Val Pro Val Gly Gly Gly 5920 5925 5930 gtg agt gtgcag gtt ggg gtt gcg gct gcg gat ggg gag ggg cgg cgt 18030 Val Ser ValGln Val Gly Val Ala Ala Ala Asp Gly Glu Gly Arg Arg 5935 5940 5945 5950ttg gtg agt gtg tat gcg cgg ggt ggg agt gct tgt ggt ggg ggt ggt 18078Leu Val Ser Val Tyr Ala Arg Gly Gly Ser Ala Cys Gly Gly Gly Gly 59555960 5965 gcg tcg ggt ggg gtg tgg acg tgt cat gcc tcg ggg gtg ctg gttgag 18126 Ala Ser Gly Gly Val Trp Thr Cys His Ala Ser Gly Val Leu ValGlu 5970 5975 5980 gct gct gct ggt ggt ggt gtg gtg gtg gat ggt ctg gcgggg gtg tgg 18174 Ala Ala Ala Gly Gly Gly Val Val Val Asp Gly Leu AlaGly Val Trp 5985 5990 5995 ccg ccg cgg ggt gcg gtg gcg gtg gat gtc gatggt gtc cgt gac cgt 18222 Pro Pro Arg Gly Ala Val Ala Val Asp Val AspGly Val Arg Asp Arg 6000 6005 6010 ttg gct ggg gct ggt tgt gtt ttg gggccg gtg ttt tcg ggg ctg cgt 18270 Leu Ala Gly Ala Gly Cys Val Leu GlyPro Val Phe Ser Gly Leu Arg 6015 6020 6025 6030 gcg gtg tgg cgt gat gggggg gat ttg ctg gct gag gtg tgt ctg ccg 18318 Ala Val Trp Arg Asp GlyGly Asp Leu Leu Ala Glu Val Cys Leu Pro 6035 6040 6045 gag gag gcg tggggt gat gcg gct ggt ttt ggg ctg cat ccg gcg ttg 18366 Glu Glu Ala TrpGly Asp Ala Ala Gly Phe Gly Leu His Pro Ala Leu 6050 6055 6060 ctg gatggt gtg gtc cag ccg ttg tcg gtg ttg ctt ccg ggt ggg acg 18414 Leu AspGly Val Val Gln Pro Leu Ser Val Leu Leu Pro Gly Gly Thr 6065 6070 6075ggg ttt ggg gag ggg gcg ggg ttc ggg gag ggt gtt cgg gtg ccg gct 18462Gly Phe Gly Glu Gly Ala Gly Phe Gly Glu Gly Val Arg Val Pro Ala 60806085 6090 gtg tgg ggt ggt gtg tcg ctt cac cgg gcg ggt gtg acc ggt gtgcgg 18510 Val Trp Gly Gly Val Ser Leu His Arg Ala Gly Val Thr Gly ValArg 6095 6100 6105 6110 gtg cgt gtg tgg gct gta ggg cgg ggc ggc ggg cgtgag gcg gtg tcg 18558 Val Arg Val Trp Ala Val Gly Arg Gly Gly Gly ArgGlu Ala Val Ser 6115 6120 6125 gtc gtg gtc ggg gat gag gcg ggt gtg ccggtg gcg tcg gtc gat cgt 18606 Val Val Val Gly Asp Glu Ala Gly Val ProVal Ala Ser Val Asp Arg 6130 6135 6140 ctt gag ttg cgg cct gtg gat atgggt cag ttg cgt gct gtc tcg gtt 18654 Leu Glu Leu Arg Pro Val Asp MetGly Gln Leu Arg Ala Val Ser Val 6145 6150 6155 tcg gcg ggg cgg cgg ggttcg ctg tat gcg gtg cag tgg gct gag gtg 18702 Ser Ala Gly Arg Arg GlySer Leu Tyr Ala Val Gln Trp Ala Glu Val 6160 6165 6170 ggt cct gtg ccggtg tgt ggg cag gcg tgg gcg tgg cac gag gac gtg 18750 Gly Pro Val ProVal Cys Gly Gln Ala Trp Ala Trp His Glu Asp Val 6175 6180 6185 6190 ggtgag agc ggt ggt ggg cct gtg ccg ggg gtg gtg gtg ttg cgg tgc 18798 GlyGlu Ser Gly Gly Gly Pro Val Pro Gly Val Val Val Leu Arg Cys 6195 62006205 ccg gat gcc ggt gcc ggt ggc ggc ggt ggc ggt ggt gtg ggt gag gtt18846 Pro Asp Ala Gly Ala Gly Gly Gly Gly Gly Gly Gly Val Gly Glu Val6210 6215 6220 gtt ggt ggg gtg ttg ggt gtg gtg cag ggg tgg ctg ggg ctggag cgg 18894 Val Gly Gly Val Leu Gly Val Val Gln Gly Trp Leu Gly LeuGlu Arg 6225 6230 6235 ttt gcg ggt tcg cgg ctg gtg gtg gtg acc cgg ggtgcg gtg gtg gcc 18942 Phe Ala Gly Ser Arg Leu Val Val Val Thr Arg GlyAla Val Val Ala 6240 6245 6250 ggc caa gaa gac ggc ccg gtg gat gtg gtgggt gcg gcg gtg tgg ggg 18990 Gly Gln Glu Asp Gly Pro Val Asp Val ValGly Ala Ala Val Trp Gly 6255 6260 6265 6270 ctg gtg cgg tcg gcg cag gctgag cat ccg gac cgg ttt gtc ctc ctc 19038 Leu Val Arg Ser Ala Gln AlaGlu His Pro Asp Arg Phe Val Leu Leu 6275 6280 6285 gac ctc gac acc gacacc gac acc ggc acc gac ctc gac acc ggt gct 19086 Asp Leu Asp Thr AspThr Asp Thr Gly Thr Asp Leu Asp Thr Gly Ala 6290 6295 6300 ggt gct ggtgct ggt gct ggt tgg ggc gtg gat ggt ggg cat gtg gcg 19134 Gly Ala GlyAla Gly Ala Gly Trp Gly Val Asp Gly Gly His Val Ala 6305 6310 6315 gcggtg gtg gcg tgt ggt gag ccg cag ttg gcg gtg cgt ggt gag cgg 19182 AlaVal Val Ala Cys Gly Glu Pro Gln Leu Ala Val Arg Gly Glu Arg 6320 63256330 gtg ctg gcc gca cgc ctg acg cga ctt gag tcg tcc gtt gat gta cct19230 Val Leu Ala Ala Arg Leu Thr Arg Leu Glu Ser Ser Val Asp Val Pro6335 6340 6345 6350 gct cag cgg tcc ggt gat gtt gct ggt cgg gag gtg ttgccg tgg ttg 19278 Ala Gln Arg Ser Gly Asp Val Ala Gly Arg Glu Val LeuPro Trp Leu 6355 6360 6365 tcg ggt ggg tcg gtg ttg gtg acg ggt ggg acgggt gtg ctg ggt gcg 19326 Ser Gly Gly Ser Val Leu Val Thr Gly Gly ThrGly Val Leu Gly Ala 6370 6375 6380 gcg gtg gcg cgg cat ctg gct ggt gtgtgt ggg gtg cgg gat ctg ctg 19374 Ala Val Ala Arg His Leu Ala Gly ValCys Gly Val Arg Asp Leu Leu 6385 6390 6395 ttg gtg agc cgg cgt ggt ccggat gct ccg ggt gcg gag ggt ttg cgg 19422 Leu Val Ser Arg Arg Gly ProAsp Ala Pro Gly Ala Glu Gly Leu Arg 6400 6405 6410 gcg gag ctg gcc gcgttg ggg gcg gag gtg cgg att gtt gcg tgt gat 19470 Ala Glu Leu Ala AlaLeu Gly Ala Glu Val Arg Ile Val Ala Cys Asp 6415 6420 6425 6430 gtg ggggag cgg cgg gag gtg gtc cgg ctg ctg gag ggt gtt cct gcc 19518 Val GlyGlu Arg Arg Glu Val Val Arg Leu Leu Glu Gly Val Pro Ala 6435 6440 6445ggg tgt ccg ctg acg ggt gtc gtg cat gcg gct ggt gtg ctg gac gat 19566Gly Cys Pro Leu Thr Gly Val Val His Ala Ala Gly Val Leu Asp Asp 64506455 6460 gcg acg atc gcc tct ctc acg ccc gag cgg ctg ggc acg gtg ttcgcg 19614 Ala Thr Ile Ala Ser Leu Thr Pro Glu Arg Leu Gly Thr Val PheAla 6465 6470 6475 gcc aag gtg gat gcc gct ctt ttg ctg gat gag ctg acgcgg ggt atg 19662 Ala Lys Val Asp Ala Ala Leu Leu Leu Asp Glu Leu ThrArg Gly Met 6480 6485 6490 gag ctg tcg gcg ttc gtg ctg ttc tcc tcg gccgcg ggg atc ctg ggg 19710 Glu Leu Ser Ala Phe Val Leu Phe Ser Ser AlaAla Gly Ile Leu Gly 6495 6500 6505 6510 tcg gcc ggg cag ggc aac tac gccgcg gcc aat gcc gct ctg gac gcg 19758 Ser Ala Gly Gln Gly Asn Tyr AlaAla Ala Asn Ala Ala Leu Asp Ala 6515 6520 6525 ctg gcg tac cgg cgg cgggcg gcg ggt ctg ccg ggg gtg tcg ctg gcg 19806 Leu Ala Tyr Arg Arg ArgAla Ala Gly Leu Pro Gly Val Ser Leu Ala 6530 6535 6540 tgg ggg ctg tgggaa gag gcc agc ggg atg acc ggg cac ctg gcc ggc 19854 Trp Gly Leu TrpGlu Glu Ala Ser Gly Met Thr Gly His Leu Ala Gly 6545 6550 6555 acc gaccac cgg cgc atc atc cgt tcc ggt ctg cat ccc atg tcg acc 19902 Thr AspHis Arg Arg Ile Ile Arg Ser Gly Leu His Pro Met Ser Thr 6560 6565 6570ccg gac gca ctg gct ctc ttc gat gcg gcc ctg gct ctg gac cgg ccg 19950Pro Asp Ala Leu Ala Leu Phe Asp Ala Ala Leu Ala Leu Asp Arg Pro 65756580 6585 6590 gtc ctg ctg ccc gcc gac ctg cgt ccc gcc ccg ccc ctg ccgccc ctg 19998 Val Leu Leu Pro Ala Asp Leu Arg Pro Ala Pro Pro Leu ProPro Leu 6595 6600 6605 ctg cag gac ctc ctg ccc gcc acc cgc cgc cgc accacc cgc acc acc 20046 Leu Gln Asp Leu Leu Pro Ala Thr Arg Arg Arg ThrThr Arg Thr Thr 6610 6615 6620 act acc ggt ggt gcg gac aac ggc gcc cagctg cat gcc cgg ctg gcc 20094 Thr Thr Gly Gly Ala Asp Asn Gly Ala GlnLeu His Ala Arg Leu Ala 6625 6630 6635 ggc cag aca cac gaa caa cag cacacc acc ctc ctc gcc ctg gtc cgc 20142 Gly Gln Thr His Glu Gln Gln HisThr Thr Leu Leu Ala Leu Val Arg 6640 6645 6650 tcc cac atc gcc acc gtcctc ggc cac acc acc ccc gac acc atc ccc 20190 Ser His Ile Ala Thr ValLeu Gly His Thr Thr Pro Asp Thr Ile Pro 6655 6660 6665 6670 ccc gac cgcgcg ttc cgc gac ctc ggc ttc gac tcc ctc acc gcc gtc 20238 Pro Asp ArgAla Phe Arg Asp Leu Gly Phe Asp Ser Leu Thr Ala Val 6675 6680 6685 gaacta cgc aac cgg ctc tcc cgc acc acc gga ctc cgc ctc ccc acc 20286 GluLeu Arg Asn Arg Leu Ser Arg Thr Thr Gly Leu Arg Leu Pro Thr 6690 66956700 acc ctc gcc ttc gac cac ccc aac ccc acc acc ctc acc cac cac ctc20334 Thr Leu Ala Phe Asp His Pro Asn Pro Thr Thr Leu Thr His His Leu6705 6710 6715 cac aca caa ctt ctg ggc tcg gac agc act gcc tcc atc ccagct ccc 20382 His Thr Gln Leu Leu Gly Ser Asp Ser Thr Ala Ser Ile ProAla Pro 6720 6725 6730 cgt gct gcg gct gtg cct gca gac cag gac gag cccgtc gcg atc att 20430 Arg Ala Ala Ala Val Pro Ala Asp Gln Asp Glu ProVal Ala Ile Ile 6735 6740 6745 6750 ggc atg gcg tgc cgc tat ccc gga ggcgtc acc tca gcc gag gag ctg 20478 Gly Met Ala Cys Arg Tyr Pro Gly GlyVal Thr Ser Ala Glu Glu Leu 6755 6760 6765 tgg gaa ctg ctc gca tcg gggagg gac acg gtc ggc gag ttt ccg acg 20526 Trp Glu Leu Leu Ala Ser GlyArg Asp Thr Val Gly Glu Phe Pro Thr 6770 6775 6780 gac cgt ggg tgg gacctg gaa gca ctg ttc gat ccg gaa ccg ggt cgg 20574 Asp Arg Gly Trp AspLeu Glu Ala Leu Phe Asp Pro Glu Pro Gly Arg 6785 6790 6795 ccg ggc acctcg tac acc cgc tgt ggg agt ttc ctc tac gac gcg ggg 20622 Pro Gly ThrSer Tyr Thr Arg Cys Gly Ser Phe Leu Tyr Asp Ala Gly 6800 6805 6810 gagttc gac gcc ggc ttc ttc ggg atc agt ccg cgt gag gca ctg gcg 20670 GluPhe Asp Ala Gly Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu Ala 6815 68206825 6830 atg gac ccg cag cag cga ttg ctg ctg gag gcc tca tgg gag gccatg 20718 Met Asp Pro Gln Gln Arg Leu Leu Leu Glu Ala Ser Trp Glu AlaMet 6835 6840 6845 gag cag gca ggt att gac cct acg acc gta cgc ggg agccag aca ggc 20766 Glu Gln Ala Gly Ile Asp Pro Thr Thr Val Arg Gly SerGln Thr Gly 6850 6855 6860 gtg ttc gcg ggc ctc att ccg cag gcc tat ggaccc agg ctg cac gaa 20814 Val Phe Ala Gly Leu Ile Pro Gln Ala Tyr GlyPro Arg Leu His Glu 6865 6870 6875 aac gcc gca gcc gac acc gag ggc tatgtc ctg acc ggc aca tcc ggg 20862 Asn Ala Ala Ala Asp Thr Glu Gly TyrVal Leu Thr Gly Thr Ser Gly 6880 6885 6890 agt gtg gcc tcc ggt cgt atctcg tac acg ttt ggt ttt gag ggt cct 20910 Ser Val Ala Ser Gly Arg IleSer Tyr Thr Phe Gly Phe Glu Gly Pro 6895 6900 6905 6910 gcg gtg tcg gtggac acg gct tgt tcc tcg tcg ttg gtg gct tta cat 20958 Ala Val Ser ValAsp Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His 6915 6920 6925 ctg gcctgt cag gcg ttg cgt gcg ggt gag tgc tcg atg gcg ctt gcc 21006 Leu AlaCys Gln Ala Leu Arg Ala Gly Glu Cys Ser Met Ala Leu Ala 6930 6935 6940ggg ggt gtg acg gtg atg tcg tct ccg ggt gcc ttc gtg gag ttt tcg 21054Gly Gly Val Thr Val Met Ser Ser Pro Gly Ala Phe Val Glu Phe Ser 69456950 6955 cgg cag cgg ggt ctg gcc gcg gac ggg cat tgc aag gcg ttc tcggcg 21102 Arg Gln Arg Gly Leu Ala Ala Asp Gly His Cys Lys Ala Phe SerAla 6960 6965 6970 gcg gcg gac ggg acc ggc tgg ggt gag ggt gtg ggg atgctg ctg gtg 21150 Ala Ala Asp Gly Thr Gly Trp Gly Glu Gly Val Gly MetLeu Leu Val 6975 6980 6985 6990 gag cgg ctc tcc gac gcc cgt cgc aac ggtcac cgt gtc ctg gcc gtg 21198 Glu Arg Leu Ser Asp Ala Arg Arg Asn GlyHis Arg Val Leu Ala Val 6995 7000 7005 gtg cgt ggc agt gcg gtc aac caggac ggt gcg agc aac ggg ctg acc 21246 Val Arg Gly Ser Ala Val Asn GlnAsp Gly Ala Ser Asn Gly Leu Thr 7010 7015 7020 gcg ccc aac ggg ccc tcccag cag cgt gtc atc cgc cag gcc ctc gcc 21294 Ala Pro Asn Gly Pro SerGln Gln Arg Val Ile Arg Gln Ala Leu Ala 7025 7030 7035 aac gcc ggc ttgtcg gcc ggt gat gtc gat gcg gtg gag gcc cac ggc 21342 Asn Ala Gly LeuSer Ala Gly Asp Val Asp Ala Val Glu Ala His Gly 7040 7045 7050 acc ggcacc act ttg ggc gac ccg atc gag gcc cag gcc ctc ctt gcg 21390 Thr GlyThr Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala 7055 7060 70657070 acc tac ggg cag gac cgt gcc ggc gag ggg ccg ctg tgg ctg ggc tcg21438 Thr Tyr Gly Gln Asp Arg Ala Gly Glu Gly Pro Leu Trp Leu Gly Ser7075 7080 7085 gtc aag tcc aat gtc ggt cac aca cag gct gcc gcg ggc gtcgcc ggg 21486 Val Lys Ser Asn Val Gly His Thr Gln Ala Ala Ala Gly ValAla Gly 7090 7095 7100 gtg atc aag atg gtg atg gcg ctg cgg aat ggt ctgctg ccg cgg acg 21534 Val Ile Lys Met Val Met Ala Leu Arg Asn Gly LeuLeu Pro Arg Thr 7105 7110 7115 ttg cat gtg gat gag ccg tcg ccg cat gtggac tgg tcc gcg ggt gcg 21582 Leu His Val Asp Glu Pro Ser Pro His ValAsp Trp Ser Ala Gly Ala 7120 7125 7130 gtg cag ctg ctg acg gag acg gtgccc tgg ccc ggc ggg gag ggg cgg 21630 Val Gln Leu Leu Thr Glu Thr ValPro Trp Pro Gly Gly Glu Gly Arg 7135 7140 7145 7150 cta cgg cgg gca ggagtg tca tca ttc ggc gtc agc ggc acc aac gcc 21678 Leu Arg Arg Ala GlyVal Ser Ser Phe Gly Val Ser Gly Thr Asn Ala 7155 7160 7165 cac gtc atcctc gaa gaa gca ccc gcc cac aac atc ccg tca gac aca 21726 His Val IleLeu Glu Glu Ala Pro Ala His Asn Ile Pro Ser Asp Thr 7170 7175 7180 cccgcc gac gac gtt ccg ggg gga cca ccc gcc ggc gag gat gcc ggt 21774 ProAla Asp Asp Val Pro Gly Gly Pro Pro Ala Gly Glu Asp Ala Gly 7185 71907195 agt ggc gag gag gct gct gcc ggc agt cca ggg gtg tgg ccg tgg ctg21822 Ser Gly Glu Glu Ala Ala Ala Gly Ser Pro Gly Val Trp Pro Trp Leu7200 7205 7210 gtg tcg gcc aag tcg cag ccg gcc ctg cgc gcc cag gcc caggcc ctg 21870 Val Ser Ala Lys Ser Gln Pro Ala Leu Arg Ala Gln Ala GlnAla Leu 7215 7220 7225 7230 cac gcc cac ctc acc gac cac ccc ggc ctc gacctc gcc gac gtc gga 21918 His Ala His Leu Thr Asp His Pro Gly Leu AspLeu Ala Asp Val Gly 7235 7240 7245 tac acc ctc gcc cac gcc cgc gcc gtgttc gac cac cgc gcc acc ctc 21966 Tyr Thr Leu Ala His Ala Arg Ala ValPhe Asp His Arg Ala Thr Leu 7250 7255 7260 atc gcc gcc gac cgc gac accttc ctg caa gca ctc cag gca ctc gcc 22014 Ile Ala Ala Asp Arg Asp ThrPhe Leu Gln Ala Leu Gln Ala Leu Ala 7265 7270 7275 gca ggc gaa ccc cacccc gcc gtc atc cac agc agc gcc cca ggc ggg 22062 Ala Gly Glu Pro HisPro Ala Val Ile His Ser Ser Ala Pro Gly Gly 7280 7285 7290 acc ggg accggg gag gcc gca gga aag acc gca ttc atc tgc tcc gga 22110 Thr Gly ThrGly Glu Ala Ala Gly Lys Thr Ala Phe Ile Cys Ser Gly 7295 7300 7305 7310cag ggc acc caa cgc ccc ggc atg gcc cac ggc ctc tac cac acc cac 22158Gln Gly Thr Gln Arg Pro Gly Met Ala His Gly Leu Tyr His Thr His 73157320 7325 ccc gtc ttc gcc gcc gca ctc aac gac atc tgc acc cac ctc gacccc 22206 Pro Val Phe Ala Ala Ala Leu Asn Asp Ile Cys Thr His Leu AspPro 7330 7335 7340 cac ctc gac cac ccc ctc ctc ccc ctc ctc acc cag gacccc aac acc 22254 His Leu Asp His Pro Leu Leu Pro Leu Leu Thr Gln AspPro Asn Thr 7345 7350 7355 cag gac acc acc acc ctc gaa gaa gcg gcc gcactg ctc cag cag acc 22302 Gln Asp Thr Thr Thr Leu Glu Glu Ala Ala AlaLeu Leu Gln Gln Thr 7360 7365 7370 ccg tac gcc cag ccc gcc ctc ttc gccttc cag gtc gcc ctc cac cgc 22350 Pro Tyr Ala Gln Pro Ala Leu Phe AlaPhe Gln Val Ala Leu His Arg 7375 7380 7385 7390 ctc ctc acc gac ggc taccac atc acc ccc cac tac tac gcc gga cac 22398 Leu Leu Thr Asp Gly TyrHis Ile Thr Pro His Tyr Tyr Ala Gly His 7395 7400 7405 tcc ctc ggc gaaatc acc gcc gcc cac ctc gcc ggc atc ctc acc ctc 22446 Ser Leu Gly GluIle Thr Ala Ala His Leu Ala Gly Ile Leu Thr Leu 7410 7415 7420 acc gacgcc acc acc ctc atc acc caa cgc gcc acc ctc atg caa acc 22494 Thr AspAla Thr Thr Leu Ile Thr Gln Arg Ala Thr Leu Met Gln Thr 7425 7430 7435atg ccc ccc ggc acc atg acc acc ctc cac acc acc ccc cac cac atc 22542Met Pro Pro Gly Thr Met Thr Thr Leu His Thr Thr Pro His His Ile 74407445 7450 acc cac cac atc acc gcc cac gaa aac gac ctc gcc atc gcc gccatc 22590 Thr His His Ile Thr Ala His Glu Asn Asp Leu Ala Ile Ala AlaIle 7455 7460 7465 7470 aac acc ccc acc tcc ctc gtc atc agc ggc acc ccccac acc gtc caa 22638 Asn Thr Pro Thr Ser Leu Val Ile Ser Gly Thr ProHis Thr Val Gln 7475 7480 7485 cac atc acc acc ctc tgc caa caa caa ggcatc aaa acc aaa acc ctc 22686 His Ile Thr Thr Leu Cys Gln Gln Gln GlyIle Lys Thr Lys Thr Leu 7490 7495 7500 ccc acc aac cac gcc ttc cac tccccc cac acc aac ccc atc ctc aac 22734 Pro Thr Asn His Ala Phe His SerPro His Thr Asn Pro Ile Leu Asn 7505 7510 7515 caa ctc cac cag cac acccaa acc ctc acc tac cac cca ccc cac acc 22782 Gln Leu His Gln His ThrGln Thr Leu Thr Tyr His Pro Pro His Thr 7520 7525 7530 ccc ctc atc accgcc aac acc cca ccc gac caa ctc ctc acc ccc cac 22830 Pro Leu Ile ThrAla Asn Thr Pro Pro Asp Gln Leu Leu Thr Pro His 7535 7540 7545 7550 tactgg acc caa caa gcc cgc aac acc gtc gac ata gcc acc acc acc 22878 TyrTrp Thr Gln Gln Ala Arg Asn Thr Val Asp Ile Ala Thr Thr Thr 7555 75607565 caa acc ctc cac caa cac ggc gtc acc acc tac atc gaa ctc gga ccc22926 Gln Thr Leu His Gln His Gly Val Thr Thr Tyr Ile Glu Leu Gly Pro7570 7575 7580 gac aac acc ctc acc acc ctc acc cac cac aac ctc ccc aacacc ccc 22974 Asp Asn Thr Leu Thr Thr Leu Thr His His Asn Leu Pro AsnThr Pro 7585 7590 7595 acc acc acc ctc acc ctc acc cac ccc cac cac cacccc caa acc cac 23022 Thr Thr Thr Leu Thr Leu Thr His Pro His His HisPro Gln Thr His 7600 7605 7610 ctc ctc acc aac ctc gcc aaa acc acc accacc tgg cac ccc cac cac 23070 Leu Leu Thr Asn Leu Ala Lys Thr Thr ThrThr Trp His Pro His His 7615 7620 7625 7630 tac acc cac cac cac aac caaccc cac acc cac acc cac ctc gac ctc 23118 Tyr Thr His His His Asn GlnPro His Thr His Thr His Leu Asp Leu 7635 7640 7645 ccc acc tac ccc ttccaa cac cac cac tac tgg ctc gaa agc aca cag 23166 Pro Thr Tyr Pro PheGln His His His Tyr Trp Leu Glu Ser Thr Gln 7650 7655 7660 ccc ggt gccggc aac gtg tca gca gcc gga ctc gac ccc acc gaa cac 23214 Pro Gly AlaGly Asn Val Ser Ala Ala Gly Leu Asp Pro Thr Glu His 7665 7670 7675 ccccta ctc ggc gcc aca ttg gaa ctg gcc gaa ggg gac ggc tgc cta 23262 ProLeu Leu Gly Ala Thr Leu Glu Leu Ala Glu Gly Asp Gly Cys Leu 7680 76857690 ctg acg ggg cgc ctc tcg ttg cgc acg cat ccc tgg ctc gcc ggc cat23310 Leu Thr Gly Arg Leu Ser Leu Arg Thr His Pro Trp Leu Ala Gly His7695 7700 7705 7710 gcg gta ggc ggt gtc gtg ctg ctg ccg ggt acg gcc ttcgcg gaa ctg 23358 Ala Val Gly Gly Val Val Leu Leu Pro Gly Thr Ala PheAla Glu Leu 7715 7720 7725 gcc ctt cat gcc gga gaa agt gtg ggt tgc gaccac gtg gac gag ctg 23406 Ala Leu His Ala Gly Glu Ser Val Gly Cys AspHis Val Asp Glu Leu 7730 7735 7740 acg ctc cac aca ccg ttg gtc att cctgag gtc gga gac gtg acc ctt 23454 Thr Leu His Thr Pro Leu Val Ile ProGlu Val Gly Asp Val Thr Leu 7745 7750 7755 cag gtt gcc att gcg gcg ccggac gag tcg ggt cgc cgc atg atg acc 23502 Gln Val Ala Ile Ala Ala ProAsp Glu Ser Gly Arg Arg Met Met Thr 7760 7765 7770 atc cac tca cgc ggtgag ggc ggc agt ggt gga gcc gat gcg tcg gcc 23550 Ile His Ser Arg GlyGlu Gly Gly Ser Gly Gly Ala Asp Ala Ser Ala 7775 7780 7785 7790 agt gcgtgg acg cgt cat gcc gcg ggt gtg ctg agc cct gcc aag gac 23598 Ser AlaTrp Thr Arg His Ala Ala Gly Val Leu Ser Pro Ala Lys Asp 7795 7800 7805gat gac act gcc tcg tac gag ctg ctt gcg gga ccc tgg cct ccc gtt 23646Asp Asp Thr Ala Ser Tyr Glu Leu Leu Ala Gly Pro Trp Pro Pro Val 78107815 7820 gga gct acg cct gtc gac ctg aac acg gct tac gat caa atg gccgac 23694 Gly Ala Thr Pro Val Asp Leu Asn Thr Ala Tyr Asp Gln Met AlaAsp 7825 7830 7835 gcc ggc ttt gct tat ggc ctg gca ttc caa ggg ttg cgcgcg gcc tgg 23742 Ala Gly Phe Ala Tyr Gly Leu Ala Phe Gln Gly Leu ArgAla Ala Trp 7840 7845 7850 cgc tac ggc gac gac atc ctc gtc gag gca cgtctt ccc gaa gaa gtg 23790 Arg Tyr Gly Asp Asp Ile Leu Val Glu Ala ArgLeu Pro Glu Glu Val 7855 7860 7865 7870 tcg gga gac gcg gcg gcg tac ggtctg cac ccg gcc ctg ctc gac gct 23838 Ser Gly Asp Ala Ala Ala Tyr GlyLeu His Pro Ala Leu Leu Asp Ala 7875 7880 7885 gcc ctt cag ggc acc ggcctg ctt tct gtg gcg ggt ccg ggg acg ccc 23886 Ala Leu Gln Gly Thr GlyLeu Leu Ser Val Ala Gly Pro Gly Thr Pro 7890 7895 7900 gtc gtg ccc catgtg tgg aac ggt ctg cgg ttc cgt acg cat ggt gca 23934 Val Val Pro HisVal Trp Asn Gly Leu Arg Phe Arg Thr His Gly Ala 7905 7910 7915 gtc tccgtg cgc gcg tgc ctg tcg acg ctt gga gcg aca ggg gcg gcc 23982 Val SerVal Arg Ala Cys Leu Ser Thr Leu Gly Ala Thr Gly Ala Ala 7920 7925 7930gtg tgc gtg cgc atc acc gac gac acc ggg gtg ccg gtg gcg tcg gtc 24030Val Cys Val Arg Ile Thr Asp Asp Thr Gly Val Pro Val Ala Ser Val 79357940 7945 7950 gat cgt ctt gag ttg cgg cct gtg gat atg ggt cag ttg cgtgct gtc 24078 Asp Arg Leu Glu Leu Arg Pro Val Asp Met Gly Gln Leu ArgAla Val 7955 7960 7965 tcg gtt tcg gcg ggg cgg cgg ggt tcg ctg tat gcggtg cag tgg gct 24126 Ser Val Ser Ala Gly Arg Arg Gly Ser Leu Tyr AlaVal Gln Trp Ala 7970 7975 7980 gag gtg ggt cct gtg ccg gtg tgt ggg caggcg tgg gcg tgg cac gag 24174 Glu Val Gly Pro Val Pro Val Cys Gly GlnAla Trp Ala Trp His Glu 7985 7990 7995 gac gtg ggt gag agc ggt ggt gggcct gtg ccg ggg gtg gtg gtg ttg 24222 Asp Val Gly Glu Ser Gly Gly GlyPro Val Pro Gly Val Val Val Leu 8000 8005 8010 cgg tgc ccg gat gcc ggtgcc gat ggc ggc ggt ggc ggt ggt gtg ggt 24270 Arg Cys Pro Asp Ala GlyAla Asp Gly Gly Gly Gly Gly Gly Val Gly 8015 8020 8025 8030 gag gtt gttggt ggg gtg ttg ggt gtg gtg cag ggg tgg ctg ggg ctg 24318 Glu Val ValGly Gly Val Leu Gly Val Val Gln Gly Trp Leu Gly Leu 8035 8040 8045 gagcgg ttt gcg ggt tcg cgg ctg gtg gtg gtg acc cgg ggt gcg gtg 24366 GluArg Phe Ala Gly Ser Arg Leu Val Val Val Thr Arg Gly Ala Val 8050 80558060 gtg gcc ggc ccg gag gac ggc ccg gtg gat gtg gtg ggt gcg gcg gtg24414 Val Ala Gly Pro Glu Asp Gly Pro Val Asp Val Val Gly Ala Ala Val8065 8070 8075 tgg ggg ctg gtg cgg tcg gcg cag gct gag cat ccg gac cggttt gtc 24462 Trp Gly Leu Val Arg Ser Ala Gln Ala Glu His Pro Asp ArgPhe Val 8080 8085 8090 ctc ctc gac ctg gac acc gac ctc gac agc ggc gctgac gcc gat gcc 24510 Leu Leu Asp Leu Asp Thr Asp Leu Asp Ser Gly AlaAsp Ala Asp Ala 8095 8100 8105 8110 ggc aac gag gcc ggt atg ggg tct ggtctg gat ggt ggg cgt gtg gct 24558 Gly Asn Glu Ala Gly Met Gly Ser GlyLeu Asp Gly Gly Arg Val Ala 8115 8120 8125 gcg gtg gtg gcg tgt ggt gagccg cag ttg gcg gtg cgt ggt gag cgg 24606 Ala Val Val Ala Cys Gly GluPro Gln Leu Ala Val Arg Gly Glu Arg 8130 8135 8140 gtg ctg gcc gca cgcctg aca cga ctt gag tcg ccg gtt gat gta tcg 24654 Val Leu Ala Ala ArgLeu Thr Arg Leu Glu Ser Pro Val Asp Val Ser 8145 8150 8155 ggt cgg gaggtg ttg ccg tgg ttg tcg ggt ggg tcg gtg ttg gtg acg 24702 Gly Arg GluVal Leu Pro Trp Leu Ser Gly Gly Ser Val Leu Val Thr 8160 8165 8170 ggtggg acg ggt gtg ctg ggt gcg gcg gtg gcg cgg cat ctg gct ggt 24750 GlyGly Thr Gly Val Leu Gly Ala Ala Val Ala Arg His Leu Ala Gly 8175 81808185 8190 gtg tgt ggg gtg cgg gat ctg ttg ttg gtg agc cgg cgt ggt ccggat 24798 Val Cys Gly Val Arg Asp Leu Leu Leu Val Ser Arg Arg Gly ProAsp 8195 8200 8205 gct ccg ggt gcg gag ggt ttg cgg gcg gag ctg gcc gcgttg ggg gcg 24846 Ala Pro Gly Ala Glu Gly Leu Arg Ala Glu Leu Ala AlaLeu Gly Ala 8210 8215 8220 gag gtg cgg att gtt gcg tgt gat gtg ggg gagcgg cgg gag gtg gtc 24894 Glu Val Arg Ile Val Ala Cys Asp Val Gly GluArg Arg Glu Val Val 8225 8230 8235 cgg ctg ctg gag ggt gtt cct gcc gggtgt ccg ctg acg ggt gtc gtg 24942 Arg Leu Leu Glu Gly Val Pro Ala GlyCys Pro Leu Thr Gly Val Val 8240 8245 8250 cat gcg gct ggt gtg ctg gacgat gcg acg atc gcc tct ctc acg ccc 24990 His Ala Ala Gly Val Leu AspAsp Ala Thr Ile Ala Ser Leu Thr Pro 8255 8260 8265 8270 gag cgg ctg ggcacg gtg ttc gcg gcc aag gtg gat gcc gct ctt ttg 25038 Glu Arg Leu GlyThr Val Phe Ala Ala Lys Val Asp Ala Ala Leu Leu 8275 8280 8285 ctg gatgag ctg acg cgg ggt atg gag ctg tcg gcg ttc gtg ctg ttc 25086 Leu AspGlu Leu Thr Arg Gly Met Glu Leu Ser Ala Phe Val Leu Phe 8290 8295 8300tcc tcg gcc gcg ggg atc ctg ggg tcg gcc ggg cag ggc aac tac gcc 25134Ser Ser Ala Ala Gly Ile Leu Gly Ser Ala Gly Gln Gly Asn Tyr Ala 83058310 8315 gcg gcc aat gcc gct ctg gac gcg ctg gcg tac cgg cgg cgg gcggcg 25182 Ala Ala Asn Ala Ala Leu Asp Ala Leu Ala Tyr Arg Arg Arg AlaAla 8320 8325 8330 ggt ctg ccg ggg gtg tcg ctg gcg tgg ggg ctg tgg gaagag gcc agc 25230 Gly Leu Pro Gly Val Ser Leu Ala Trp Gly Leu Trp GluGlu Ala Ser 8335 8340 8345 8350 ggg atg acc ggg cac ctg gcc ggc acc gaccac cgg cgc atc atc cgt 25278 Gly Met Thr Gly His Leu Ala Gly Thr AspHis Arg Arg Ile Ile Arg 8355 8360 8365 tcc ggt ctg cat ccc atg tcg accccg gac gca ctg gct ctc ttc gat 25326 Ser Gly Leu His Pro Met Ser ThrPro Asp Ala Leu Ala Leu Phe Asp 8370 8375 8380 gcg gcc ctg gct ctg gaccgg ccg gtc ctg ctg ccc gcc gac ctg cgt 25374 Ala Ala Leu Ala Leu AspArg Pro Val Leu Leu Pro Ala Asp Leu Arg 8385 8390 8395 ccc gcc ccg cccctg ccg ccc ctg ctg cag gac ctc ctg ccc gcc acc 25422 Pro Ala Pro ProLeu Pro Pro Leu Leu Gln Asp Leu Leu Pro Ala Thr 8400 8405 8410 cgc cgccgc acc acc cgc acc acc act acc ggt ggt gcg gac aac ggc 25470 Arg ArgArg Thr Thr Arg Thr Thr Thr Thr Gly Gly Ala Asp Asn Gly 8415 8420 84258430 gcc cag ctg cat gcc cgg ctg gcc ggc cag aca cac gaa caa cag cac25518 Ala Gln Leu His Ala Arg Leu Ala Gly Gln Thr His Glu Gln Gln His8435 8440 8445 acc acc ctc ctc gcc ctg gtc cgc tcc cac atc gcc acc gtcctc ggc 25566 Thr Thr Leu Leu Ala Leu Val Arg Ser His Ile Ala Thr ValLeu Gly 8450 8455 8460 cac aac gcg ccg gag atg atc ccc gtt gac tcg gcgttc cgc gac cta 25614 His Asn Ala Pro Glu Met Ile Pro Val Asp Ser AlaPhe Arg Asp Leu 8465 8470 8475 ggc ttc gac tcc ttg aca gcg gtg gaa ctccgt aac cgc ctg ggt gag 25662 Gly Phe Asp Ser Leu Thr Ala Val Glu LeuArg Asn Arg Leu Gly Glu 8480 8485 8490 gca acg gga ctg cga ctg ccg accagt ctg gtc ttc gac cag ccg aat 25710 Ala Thr Gly Leu Arg Leu Pro ThrSer Leu Val Phe Asp Gln Pro Asn 8495 8500 8505 8510 gca gcg acc ctg gcgcgt cac cta cgt cgt gag ctg atg ggc gac gac 25758 Ala Ala Thr Leu AlaArg His Leu Arg Arg Glu Leu Met Gly Asp Asp 8515 8520 8525 gcg gaa ggcgag acg cca tcg cag gtc gca ctt cat cag gtt gcc gcg 25806 Ala Glu GlyGlu Thr Pro Ser Gln Val Ala Leu His Gln Val Ala Ala 8530 8535 8540 gatgag ccg att gcg att gtg ggg atg gcg tgt cgt ttt ccg ggt ggg 25854 AspGlu Pro Ile Ala Ile Val Gly Met Ala Cys Arg Phe Pro Gly Gly 8545 85508555 gtg tgt tcg ccg gag gag ttg tgg gag ctg gtt gcg tcg ggt ggg gat25902 Val Cys Ser Pro Glu Glu Leu Trp Glu Leu Val Ala Ser Gly Gly Asp8560 8565 8570 gcg att ggt gaa ttt ccg gcc ggt cgg ggg tgg gat ctg gagggg ttg 25950 Ala Ile Gly Glu Phe Pro Ala Gly Arg Gly Trp Asp Leu GluGly Leu 8575 8580 8585 8590 ttt gat tcg gac cct gac cgg tcg ggg acg tcgtac gcg cgg tat ggc 25998 Phe Asp Ser Asp Pro Asp Arg Ser Gly Thr SerTyr Ala Arg Tyr Gly 8595 8600 8605 ggg ttt ttg tat gag gcg ggg gag ttcgat gcg gac ttc ttc ggg atc 26046 Gly Phe Leu Tyr Glu Ala Gly Glu PheAsp Ala Asp Phe Phe Gly Ile 8610 8615 8620 agt ccg cgt gag gcg ttg gcgatg gat ccg cag cag cgg ttg ttg ctg 26094 Ser Pro Arg Glu Ala Leu AlaMet Asp Pro Gln Gln Arg Leu Leu Leu 8625 8630 8635 gag acg tcg tgg gaggcg ttc gag cgg gcg ggt atc gat ccg ctg tcg 26142 Glu Thr Ser Trp GluAla Phe Glu Arg Ala Gly Ile Asp Pro Leu Ser 8640 8645 8650 atg cgt ggctcc cgt acg ggt gtc ttc gcc ggg gtg atg tac cac gac 26190 Met Arg GlySer Arg Thr Gly Val Phe Ala Gly Val Met Tyr His Asp 8655 8660 8665 8670tac gcc gcg cgt ctc cac cat gtc ccc gag ggt ttc gaa ggc ctc atc 26238Tyr Ala Ala Arg Leu His His Val Pro Glu Gly Phe Glu Gly Leu Ile 86758680 8685 gcc aac ggc agc gca ggc agc gtc gcg acc ggc cgg gtg gcc tacagc 26286 Ala Asn Gly Ser Ala Gly Ser Val Ala Thr Gly Arg Val Ala TyrSer 8690 8695 8700 ttt ggc ctt gag ggt ccg gcc gtg acc gtc gat acg gcgtgt tcg tcg 26334 Phe Gly Leu Glu Gly Pro Ala Val Thr Val Asp Thr AlaCys Ser Ser 8705 8710 8715 tcg ttg gtg gcg ttg cat tgg gcg gcg cag gcgttg cgt gcg ggt gag 26382 Ser Leu Val Ala Leu His Trp Ala Ala Gln AlaLeu Arg Ala Gly Glu 8720 8725 8730 tgt tcg atg gcg ctt gcc ggg ggt gtgacg gtg atg tcg tct ccg ggt 26430 Cys Ser Met Ala Leu Ala Gly Gly ValThr Val Met Ser Ser Pro Gly 8735 8740 8745 8750 acg ttt gtg gag ttc tcacgt cag cgg ggt ctg gcc gcg gac ggg cgg 26478 Thr Phe Val Glu Phe SerArg Gln Arg Gly Leu Ala Ala Asp Gly Arg 8755 8760 8765 tgc aag gcc tattcg gcg gct gct gac ggt acc ggc tgg gcc gag ggt 26526 Cys Lys Ala TyrSer Ala Ala Ala Asp Gly Thr Gly Trp Ala Glu Gly 8770 8775 8780 gtg gggatg ctg ctg gtg gag cgg ctc tcc gac gcc cgt cgc aac ggt 26574 Val GlyMet Leu Leu Val Glu Arg Leu Ser Asp Ala Arg Arg Asn Gly 8785 8790 8795cac cgt gtc ctg gcc gtg gtg cgt ggc agt gcg gtc aac cag gac ggt 26622His Arg Val Leu Ala Val Val Arg Gly Ser Ala Val Asn Gln Asp Gly 88008805 8810 gcg agc aac ggt ctg acc gcg ccc aac ggg ccc tcc cag cag cgtgtc 26670 Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro Ser Gln Gln ArgVal 8815 8820 8825 8830 atc cgt cag gcc ctg gcc aat gcg gga ctg acc ccggcc gat gtc gac 26718 Ile Arg Gln Ala Leu Ala Asn Ala Gly Leu Thr ProAla Asp Val Asp 8835 8840 8845 gca gtg gag ggc cac ggc acc ggg acc actctg ggg gac ccg atc gag 26766 Ala Val Glu Gly His Gly Thr Gly Thr ThrLeu Gly Asp Pro Ile Glu 8850 8855 8860 gcc cag gca ctc ctg gcc gcc tacgga caa cac cgc ccc cac cac cgc 26814 Ala Gln Ala Leu Leu Ala Ala TyrGly Gln His Arg Pro His His Arg 8865 8870 8875 ccc ttg tgg ctg gga tccctc aaa tcc aac atc ggg cac gca cag gcc 26862 Pro Leu Trp Leu Gly SerLeu Lys Ser Asn Ile Gly His Ala Gln Ala 8880 8885 8890 gcc gcg ggc gtgggc gga gtc atc aag atg gtg atg gcc ctg cgc aac 26910 Ala Ala Gly ValGly Gly Val Ile Lys Met Val Met Ala Leu Arg Asn 8895 8900 8905 8910 gggctg ctg cca cag acc ctc cac gtg gac gag ccc acc ccc cag gtc 26958 GlyLeu Leu Pro Gln Thr Leu His Val Asp Glu Pro Thr Pro Gln Val 8915 89208925 gac tgg tcc aca ggc gca gta caa ctc ctg aca caa ccg gtg ccc tgg27006 Asp Trp Ser Thr Gly Ala Val Gln Leu Leu Thr Gln Pro Val Pro Trp8930 8935 8940 ccc gcc gac ccg gcc ggc cgg cca cgc cac gcc ggc gtg tcatca ttc 27054 Pro Ala Asp Pro Ala Gly Arg Pro Arg His Ala Gly Val SerSer Phe 8945 8950 8955 ggc gtc agc ggc acc aac gcc cat gtg att ttg gaggag gcg cct gcg 27102 Gly Val Ser Gly Thr Asn Ala His Val Ile Leu GluGlu Ala Pro Ala 8960 8965 8970 gcg gcg ggc ggt gct gcc ggt ggt ggg gtgtcg gtg ggt gct ccg aat 27150 Ala Ala Gly Gly Ala Ala Gly Gly Gly ValSer Val Gly Ala Pro Asn 8975 8980 8985 8990 cca gcc ctt ccg gtg gct gagtct gag ccg gtg ccg gtg ccg gtg ccg 27198 Pro Ala Leu Pro Val Ala GluSer Glu Pro Val Pro Val Pro Val Pro 8995 9000 9005 gtg tcg gcg agg tctgag gcc ggg ttg cgg gcg cag gca cag gcg ttg 27246 Val Ser Ala Arg SerGlu Ala Gly Leu Arg Ala Gln Ala Gln Ala Leu 9010 9015 9020 cgc cag tacgtg gca gcc cgc ccg gac atg tca cct gcc gac atc ggt 27294 Arg Gln TyrVal Ala Ala Arg Pro Asp Met Ser Pro Ala Asp Ile Gly 9025 9030 9035 gcgggt ctg gcc cgc ggc cgg gcc gta ctg gaa cac cgc gcc gtc atc 27342 AlaGly Leu Ala Arg Gly Arg Ala Val Leu Glu His Arg Ala Val Ile 9040 90459050 ctg gcc gcg gac cgc gag gaa ctg gcg cag gca ctg aca gcc ctg gca27390 Leu Ala Ala Asp Arg Glu Glu Leu Ala Gln Ala Leu Thr Ala Leu Ala9055 9060 9065 9070 gcc ggc gaa ccc cac ccc cac atc acc aca ggc cac acccgg ggc agt 27438 Ala Gly Glu Pro His Pro His Ile Thr Thr Gly His ThrArg Gly Ser 9075 9080 9085 gac cgc ggc ggc gtc gtc ttc gtc ttc ccc ggacag ggc ggc cag tgg 27486 Asp Arg Gly Gly Val Val Phe Val Phe Pro GlyGln Gly Gly Gln Trp 9090 9095 9100 gcc ggg atg ggc ctg acc ctg ctc acctcc tca ccc gtg ttc gcc gaa 27534 Ala Gly Met Gly Leu Thr Leu Leu ThrSer Ser Pro Val Phe Ala Glu 9105 9110 9115 cac atc gac gca tgc gag aaagcc ctc acc ccc tgg gtg ccc tgg tcc 27582 His Ile Asp Ala Cys Glu LysAla Leu Thr Pro Trp Val Pro Trp Ser 9120 9125 9130 ctg acc gac atc ctgcac cgc gac ccc gac gac ccc gca tgg caa caa 27630 Leu Thr Asp Ile LeuHis Arg Asp Pro Asp Asp Pro Ala Trp Gln Gln 9135 9140 9145 9150 gcc gacgtg gtc cag ccc gtg ctc ttc agc atc atg gtc tcc ctc gcc 27678 Ala AspVal Val Gln Pro Val Leu Phe Ser Ile Met Val Ser Leu Ala 9155 9160 9165gcc ctg tgg cgc tcc tac ggc atc gaa ccc gac gcg gtc ctc ggc cac 27726Ala Leu Trp Arg Ser Tyr Gly Ile Glu Pro Asp Ala Val Leu Gly His 91709175 9180 tcc cag gga gaa atc gcc gcc gcc cac atc tgc ggc gca ctc agcctg 27774 Ser Gln Gly Glu Ile Ala Ala Ala His Ile Cys Gly Ala Leu SerLeu 9185 9190 9195 aaa gac gcc gcc aaa acc gtt gca ctg cgc agc cag gcactg gcc gcc 27822 Lys Asp Ala Ala Lys Thr Val Ala Leu Arg Ser Gln AlaLeu Ala Ala 9200 9205 9210 gta cga ggc cgg ggc gcc atg gtc tca ctg cccctg ccc gcc cag gac 27870 Val Arg Gly Arg Gly Ala Met Val Ser Leu ProLeu Pro Ala Gln Asp 9215 9220 9225 9230 gtg cag cag ctc att tcc gaa cggtgg gaa ggg cag ttg tgg gtg gca 27918 Val Gln Gln Leu Ile Ser Glu ArgTrp Glu Gly Gln Leu Trp Val Ala 9235 9240 9245 gcc ctc aac ggc ccc cactcc acc acc gtc tcc ggc gac acc acc gca 27966 Ala Leu Asn Gly Pro HisSer Thr Thr Val Ser Gly Asp Thr Thr Ala 9250 9255 9260 gta gaa gaa ctcctc acc cac tgt gcc gac acc ggc cta cgg gcc aaa 28014 Val Glu Glu LeuLeu Thr His Cys Ala Asp Thr Gly Leu Arg Ala Lys 9265 9270 9275 cgc atcccc gtc gac tac gcc tcc cac tgc ccc cac gtc caa ccc ctc 28062 Arg IlePro Val Asp Tyr Ala Ser His Cys Pro His Val Gln Pro Leu 9280 9285 9290cac gac gaa ctc ctg cac ctg ctg gga gac atc acc ccc cag ccg tcc 28110His Asp Glu Leu Leu His Leu Leu Gly Asp Ile Thr Pro Gln Pro Ser 92959300 9305 9310 acc atg ccg ttc ttc tcc acc gtc gta ggg cac ctg gtc tggtac acc 28158 Thr Met Pro Phe Phe Ser Thr Val Val Gly His Leu Val TrpTyr Thr 9315 9320 9325 aca acc ctg gac gcc gcc tac tgg tac cgc aac ctccac cag ccc gtc 28206 Thr Thr Leu Asp Ala Ala Tyr Trp Tyr Arg Asn LeuHis Gln Pro Val 9330 9335 9340 cgc ttc agc cac gcc atc cag acc ctg accgac gac gga cac cgc ccc 28254 Arg Phe Ser His Ala Ile Gln Thr Leu ThrAsp Asp Gly His Arg Pro 9345 9350 9355 ttc atc gaa atc agt ccc cac cccacc ctc gtc ccc gcc atc gaa gac 28302 Phe Ile Glu Ile Ser Pro His ProThr Leu Val Pro Ala Ile Glu Asp 9360 9365 9370 acc acc gaa aac acc accgaa aac atc acc gcg acc ggc agc ctc cgc 28350 Thr Thr Glu Asn Thr ThrGlu Asn Ile Thr Ala Thr Gly Ser Leu Arg 9375 9380 9385 9390 cgc ggc gacaac gac acc cac cgc ttc ctc acc gcc ctc gcc cac acc 28398 Arg Gly AspAsn Asp Thr His Arg Phe Leu Thr Ala Leu Ala His Thr 9395 9400 9405 cacacc acc ggc att cgg aca ccc acc acc tgg cac cac cac tac acc 28446 HisThr Thr Gly Ile Arg Thr Pro Thr Thr Trp His His His Tyr Thr 9410 94159420 caa acc cac ccc cac ccc cac aac cac cac ctc gac ctg ccc acc tac28494 Gln Thr His Pro His Pro His Asn His His Leu Asp Leu Pro Thr Tyr9425 9430 9435 ccc ttc caa cac cag cac tac tgg ctc caa cca ccc acc acgaca acc 28542 Pro Phe Gln His Gln His Tyr Trp Leu Gln Pro Pro Thr ThrThr Thr 9440 9445 9450 gac ctc acc acc acc ggc ctc acc ccc acc cac cacccc ctc ctc acc 28590 Asp Leu Thr Thr Thr Gly Leu Thr Pro Thr His HisPro Leu Leu Thr 9455 9460 9465 9470 gca aca ctc acc ctc gcc aac aac aacaca caa cta ctc acc ggc cgc 28638 Ala Thr Leu Thr Leu Ala Asn Asn AsnThr Gln Leu Leu Thr Gly Arg 9475 9480 9485 ctc tcc cta cgc acc cac ccctgg ctc acc gac cac acc gtc gtc ggt 28686 Leu Ser Leu Arg Thr His ProTrp Leu Thr Asp His Thr Val Val Gly 9490 9495 9500 acc act ctt gtg ccagga acc gcc ctc ctc gaa ctc gcc ctc caa gca 28734 Thr Thr Leu Val ProGly Thr Ala Leu Leu Glu Leu Ala Leu Gln Ala 9505 9510 9515 acc acg accgac cac ctc gaa gaa ctc gcc ctc cac acg cct ctc gtc 28782 Thr Thr ThrAsp His Leu Glu Glu Leu Ala Leu His Thr Pro Leu Val 9520 9525 9530 atcccc cgt gag ggt gcc gtc gac gtt cag gtg cac atc aat cca ccg 28830 IlePro Arg Glu Gly Ala Val Asp Val Gln Val His Ile Asn Pro Pro 9535 95409545 9550 gac gac acc gac act cgt tca ctg acg atc tac tcg cga agc gagaac 28878 Asp Asp Thr Asp Thr Arg Ser Leu Thr Ile Tyr Ser Arg Ser GluAsn 9555 9560 9565 gcc ccc gca gcg gct ccc tgg cgt cat cac gcc acg gccgtt ctg gga 28926 Ala Pro Ala Ala Ala Pro Trp Arg His His Ala Thr AlaVal Leu Gly 9570 9575 9580 acc aag acc tcg cgc att gag aca ggc cgt agccac gat gat ctg tcg 28974 Thr Lys Thr Ser Arg Ile Glu Thr Gly Arg SerHis Asp Asp Leu Ser 9585 9590 9595 atg tgg ccg cca gcg ggc gca gtt cgctgt gct gat gag gaa ttg gca 29022 Met Trp Pro Pro Ala Gly Ala Val ArgCys Ala Asp Glu Glu Leu Ala 9600 9605 9610 gcc ttg tat ggc gac tac gaggca aat ggc ttt gtc tat ggc ccc gca 29070 Ala Leu Tyr Gly Asp Tyr GluAla Asn Gly Phe Val Tyr Gly Pro Ala 9615 9620 9625 9630 ttc cgg ggg ctgact gct gcc tgg cgt ctg gga gac gag gtg ttt gcc 29118 Phe Arg Gly LeuThr Ala Ala Trp Arg Leu Gly Asp Glu Val Phe Ala 9635 9640 9645 gag gttcgc ctt cca gaa cag gtg cac ggc gag gca tcc gcg tac aac 29166 Glu ValArg Leu Pro Glu Gln Val His Gly Glu Ala Ser Ala Tyr Asn 9650 9655 9660ctg cac ccg gca ctg ctg gat gct gcc ttg cac gca gcg gcc ttt gcg 29214Leu His Pro Ala Leu Leu Asp Ala Ala Leu His Ala Ala Ala Phe Ala 96659670 9675 ccg tcg ggc agt ctg ccg cag gga tcc gta ccg ttc tcc ttc accggt 29262 Pro Ser Gly Ser Leu Pro Gln Gly Ser Val Pro Phe Ser Phe ThrGly 9680 9685 9690 gtg acg ctg cac gcc gcc aat gcg tcg tcg ttg cgc gtgcga ctc tcg 29310 Val Thr Leu His Ala Ala Asn Ala Ser Ser Leu Arg ValArg Leu Ser 9695 9700 9705 9710 ccg gcc gat ccg aac agc ggc cac gcc gcagtt tcc gtg ctg gtc acg 29358 Pro Ala Asp Pro Asn Ser Gly His Ala AlaVal Ser Val Leu Val Thr 9715 9720 9725 gat gac acc ggt acg ccc gtg gcgtcc gtc gag gcg ttg gcg gtg cgc 29406 Asp Asp Thr Gly Thr Pro Val AlaSer Val Glu Ala Leu Ala Val Arg 9730 9735 9740 ccg ttg gcg gcg gac gaattg cga gct gcc gag cgc gcc gta cag cgc 29454 Pro Leu Ala Ala Asp GluLeu Arg Ala Ala Glu Arg Ala Val Gln Arg 9745 9750 9755 gct gag ctc ttcgac atg aag tgg gtt gag gtg ccc tca gat gta ctg 29502 Ala Glu Leu PheAsp Met Lys Trp Val Glu Val Pro Ser Asp Val Leu 9760 9765 9770 gtg tcgggc ggg gca tcg gtg gtg gtg ctg gat ggt gcc gac gac ctc 29550 Val SerGly Gly Ala Ser Val Val Val Leu Asp Gly Ala Asp Asp Leu 9775 9780 97859790 gtt ggt ctg gcg gct gag gag gat ggt gtg ccg ggg gtg gtg gtg ttg29598 Val Gly Leu Ala Ala Glu Glu Asp Gly Val Pro Gly Val Val Val Leu9795 9800 9805 cgg tgc ccg gat gcc ggt gcc gat ggc ggc ggt ggt ggc ggtggt gtg 29646 Arg Cys Pro Asp Ala Gly Ala Asp Gly Gly Gly Gly Gly GlyGly Val 9810 9815 9820 ggt gag gtt gtt ggt ggg gtg ttg ggt gtg gtg cagggg tgg ctg ggg 29694 Gly Glu Val Val Gly Gly Val Leu Gly Val Val GlnGly Trp Leu Gly 9825 9830 9835 ctg gag cgg ttt gcg ggt tcg cgg ctg gtggtg gtg acc cgg ggt gcg 29742 Leu Glu Arg Phe Ala Gly Ser Arg Leu ValVal Val Thr Arg Gly Ala 9840 9845 9850 gtg gtg gcc ggc ccg gag gac ggcccg gtg gat ggc ccg gtg gat gtg 29790 Val Val Ala Gly Pro Glu Asp GlyPro Val Asp Gly Pro Val Asp Val 9855 9860 9865 9870 gtg ggt gcg gcg gtgtgg ggg ctg gtg cgg tcg gcg cag gct gag cat 29838 Val Gly Ala Ala ValTrp Gly Leu Val Arg Ser Ala Gln Ala Glu His 9875 9880 9885 ccg gac cggttt gtc ctc ctc gac ctg gac acc gac ctc gac agc ggc 29886 Pro Asp ArgPhe Val Leu Leu Asp Leu Asp Thr Asp Leu Asp Ser Gly 9890 9895 9900 gctgac cgc gat gcc ggc aac gag gcc ggt atg ggg tct ggt ctg gat 29934 AlaAsp Arg Asp Ala Gly Asn Glu Ala Gly Met Gly Ser Gly Leu Asp 9905 99109915 ggt ggg cgt gtg gct gcg gtg gtg gcg tgt ggt gag ccg cag ttg gcg29982 Gly Gly Arg Val Ala Ala Val Val Ala Cys Gly Glu Pro Gln Leu Ala9920 9925 9930 gtg cgt ggt gag cgg gtg ctg gcc gca cgc ctg aca cga cttgag tcg 30030 Val Arg Gly Glu Arg Val Leu Ala Ala Arg Leu Thr Arg LeuGlu Ser 9935 9940 9945 9950 ccg gtt gat gta tcg ggt cgg gag gtg ttg ccgtgg ttg tcg ggt ggg 30078 Pro Val Asp Val Ser Gly Arg Glu Val Leu ProTrp Leu Ser Gly Gly 9955 9960 9965 tcg gtg ttg gtg acg ggt ggg acg ggtgtg ctg ggt gcg gcg gtg gcg 30126 Ser Val Leu Val Thr Gly Gly Thr GlyVal Leu Gly Ala Ala Val Ala 9970 9975 9980 cgg cat ctg gct ggt gtg tgtggg gtg cgg gat ctg ttg ttg gtg agc 30174 Arg His Leu Ala Gly Val CysGly Val Arg Asp Leu Leu Leu Val Ser 9985 9990 9995 cgg cgt ggt ccg gatgct ccg ggt gcg gag ggt ttg cgg gcg gag ctg 30222 Arg Arg Gly Pro AspAla Pro Gly Ala Glu Gly Leu Arg Ala Glu Leu 10000 10005 10010 gcc gcgttg ggg gcg gag gtg cgg att gtt gcg tgt gat gtg ggg gag 30270 Ala AlaLeu Gly Ala Glu Val Arg Ile Val Ala Cys Asp Val Gly Glu 10015 1002010025 10030 cgg cgg gag gtg gtc cgg ctg ctg gag ggt gtt cct gcc ggg tgtccg 30318 Arg Arg Glu Val Val Arg Leu Leu Glu Gly Val Pro Ala Gly CysPro 10035 10040 10045 ctg acg ggt gtc gtg cat gcg gct ggt gtg ctg gacgat gcg acg atc 30366 Leu Thr Gly Val Val His Ala Ala Gly Val Leu AspAsp Ala Thr Ile 10050 10055 10060 gcc tct ctc acg ccc gag cgg ctg ggcacg gtg ttc gcg gcc aag gtg 30414 Ala Ser Leu Thr Pro Glu Arg Leu GlyThr Val Phe Ala Ala Lys Val 10065 10070 10075 gat gcc gct ctt ttg ctggat gag ctg acg cgg ggt atg gag ctg tcg 30462 Asp Ala Ala Leu Leu LeuAsp Glu Leu Thr Arg Gly Met Glu Leu Ser 10080 10085 10090 gcg ttc gtgctg ttc tcc tcg gcc gcg ggg atc ctg ggg tcg gcc ggg 30510 Ala Phe ValLeu Phe Ser Ser Ala Ala Gly Ile Leu Gly Ser Ala Gly 10095 10100 1010510110 cag ggc aac tac gcc gcg gcc aat gcc gct ctg gac gcg ctg gcg tac30558 Gln Gly Asn Tyr Ala Ala Ala Asn Ala Ala Leu Asp Ala Leu Ala Tyr10115 10120 10125 cgg cgg cgg gcg gcg ggt ctg ccg ggg gtg tcg ctg gcgtgg ggg ctg 30606 Arg Arg Arg Ala Ala Gly Leu Pro Gly Val Ser Leu AlaTrp Gly Leu 10130 10135 10140 tgg gaa gag gcc agc ggg atg acc ggg catctg gcc ggc acc gac cac 30654 Trp Glu Glu Ala Ser Gly Met Thr Gly HisLeu Ala Gly Thr Asp His 10145 10150 10155 cgg cgc atc atc cgt tcc ggtctg cat ccc atg tcg acc ccg gac gca 30702 Arg Arg Ile Ile Arg Ser GlyLeu His Pro Met Ser Thr Pro Asp Ala 10160 10165 10170 ctg gcc ctc ttcgat gcg gcc ctg gct ctg gac cgg ccg gtc ctg ctg 30750 Leu Ala Leu PheAsp Ala Ala Leu Ala Leu Asp Arg Pro Val Leu Leu 10175 10180 10185 10190ccc gcc gac ctg cgt ccc gcc ccg ccc ctg ccg ccc ctg ctg cag gac 30798Pro Ala Asp Leu Arg Pro Ala Pro Pro Leu Pro Pro Leu Leu Gln Asp 1019510200 10205 ctc ctg ccc gcc acc cgc cgc cgc acc acc cgc acc acc act accggt 30846 Leu Leu Pro Ala Thr Arg Arg Arg Thr Thr Arg Thr Thr Thr ThrGly 10210 10215 10220 ggt gcg gac aac ggc gcc cag ctg cac ggc cgg ctggcc ggc cag aca 30894 Gly Ala Asp Asn Gly Ala Gln Leu His Gly Arg LeuAla Gly Gln Thr 10225 10230 10235 cac gaa caa cag cac acc acc ctc ctcgcc ctg gtc cgc tcc cac atc 30942 His Glu Gln Gln His Thr Thr Leu LeuAla Leu Val Arg Ser His Ile 10240 10245 10250 gcc acc gtc ctg ggc cacacc acc ccc gac acc atc ccc ccc gac cgc 30990 Ala Thr Val Leu Gly HisThr Thr Pro Asp Thr Ile Pro Pro Asp Arg 10255 10260 10265 10270 gcg ttccgc gac ctc ggc ttc gac tcc ctc acc gcc gtc gaa cta cgc 31038 Ala PheArg Asp Leu Gly Phe Asp Ser Leu Thr Ala Val Glu Leu Arg 10275 1028010285 aac cgg ctc tcc cac acc acc gga ctc cgc ctc ccc acc acc ctc gcc31086 Asn Arg Leu Ser His Thr Thr Gly Leu Arg Leu Pro Thr Thr Leu Ala10290 10295 10300 ttc gac cac ccc aac ccc acc acc ctc acc cac cac ctccac aca caa 31134 Phe Asp His Pro Asn Pro Thr Thr Leu Thr His His LeuHis Thr Gln 10305 10310 10315 ctc gtc agc aag gga ctc acc gcc gcg gccgag ccg gac gcc gca acg 31182 Leu Val Ser Lys Gly Leu Thr Ala Ala AlaGlu Pro Asp Ala Ala Thr 10320 10325 10330 aca ccc ccg ggg ctg ccc tcgctg ctc tcg gag ctc gag cgg ctg gag 31230 Thr Pro Pro Gly Leu Pro SerLeu Leu Ser Glu Leu Glu Arg Leu Glu 10335 10340 10345 10350 gcg gta gtgctc tcc tcc acc aca tcc tcc gct gcc ccg ctg gac gac 31278 Ala Val ValLeu Ser Ser Thr Thr Ser Ser Ala Ala Pro Leu Asp Asp 10355 10360 10365ggc gcg cgc acg cgg ctg gcc tcc cga ctg cat tcc ctc gcc cag aag 31326Gly Ala Arg Thr Arg Leu Ala Ser Arg Leu His Ser Leu Ala Gln Lys 1037010375 10380 ttg aac ggc gac gac acc gcc ccc gac ctc gca gag aca tcg gacgag 31374 Leu Asn Gly Asp Asp Thr Ala Pro Asp Leu Ala Glu Thr Ser AspGlu 10385 10390 10395 gag atg ttc gct ctc atc gac agg gaa gtc gga ttcgaa tct caa tga 31422 Glu Met Phe Ala Leu Ile Asp Arg Glu Val Gly PheGlu Ser Gln 10400 10405 10410 3 11916 DNA Artificial SequenceDescription of Artificial Sequence In vitro mutagenized DNA 3 gtg cagagg atg gac ggc ggg gaa gaa ccc cgc cct gcg gca ggg gag 48 Val Gln ArgMet Asp Gly Gly Glu Glu Pro Arg Pro Ala Ala Gly Glu 1 5 10 15 gtc ctcgga gtg gcc gac gag gcg gac ggc ggc gtc gtc ttc gtt ttt 96 Val Leu GlyVal Ala Asp Glu Ala Asp Gly Gly Val Val Phe Val Phe 20 25 30 ccc ggg cagggc ccg caa tgg ccg ggc atg gga agg gaa ctt ctc gac 144 Pro Gly Gln GlyPro Gln Trp Pro Gly Met Gly Arg Glu Leu Leu Asp 35 40 45 gct tcc gac gtcttc cgg gag agc gtc cgc gcc tgc gaa gcc gcg ttc 192 Ala Ser Asp Val PheArg Glu Ser Val Arg Ala Cys Glu Ala Ala Phe 50 55 60 gcg ccc tac gtc gactgg tcg gtg gag cag gtg ttg cgg gac tcg ccg 240 Ala Pro Tyr Val Asp TrpSer Val Glu Gln Val Leu Arg Asp Ser Pro 65 70 75 80 gac gct ccc ggg ctggac cgg gtg gac gtc gtc cag ccg acc ctg ttc 288 Asp Ala Pro Gly Leu AspArg Val Asp Val Val Gln Pro Thr Leu Phe 85 90 95 gcc gtc atg atc tcc ctggcc gcc ctc tgg cgc tcg caa ggg gtc gag 336 Ala Val Met Ile Ser Leu AlaAla Leu Trp Arg Ser Gln Gly Val Glu 100 105 110 ccg tgc gcg gtg ctg ggacac agc ctg ggc gag atc gcg gca gcc cac 384 Pro Cys Ala Val Leu Gly HisSer Leu Gly Glu Ile Ala Ala Ala His 115 120 125 gtc tcg gga ggc ctg tccctg gcc gac gcc gca cgc gtg gtg acg ctt 432 Val Ser Gly Gly Leu Ser LeuAla Asp Ala Ala Arg Val Val Thr Leu 130 135 140 tgg agc cag gca cag accacc ctt gcc ggg acc ggc gcg ctc gtc tcc 480 Trp Ser Gln Ala Gln Thr ThrLeu Ala Gly Thr Gly Ala Leu Val Ser 145 150 155 160 gtc gcc gcc acg ccggat gag ctc ctg ccc cga atc gct ccg tgg acc 528 Val Ala Ala Thr Pro AspGlu Leu Leu Pro Arg Ile Ala Pro Trp Thr 165 170 175 gag gac aac ccg gcgcgg ctc gcc gtc gca gcc gtc aac gga ccc cgg 576 Glu Asp Asn Pro Ala ArgLeu Ala Val Ala Ala Val Asn Gly Pro Arg 180 185 190 agc aca gtc gtt tccggt gcc cgc gag gcc gtc gcg gac ctg gtg gcc 624 Ser Thr Val Val Ser GlyAla Arg Glu Ala Val Ala Asp Leu Val Ala 195 200 205 gac ctc acc gcc gcgcag gtg cgc acg cgc atg atc ccg gtg gac gtt 672 Asp Leu Thr Ala Ala GlnVal Arg Thr Arg Met Ile Pro Val Asp Val 210 215 220 ccc gcc cac tcc cccctg atg tac gcc atc gag gaa cgg gtc gtc agc 720 Pro Ala His Ser Pro LeuMet Tyr Ala Ile Glu Glu Arg Val Val Ser 225 230 235 240 ggc ctg ctg cccatc acc cca cgc ccc tcc cgc atc ccc ttc cac tcc 768 Gly Leu Leu Pro IleThr Pro Arg Pro Ser Arg Ile Pro Phe His Ser 245 250 255 tcg gtg acc ggcggc cgc ctc gac acc cgc gag cta gac gcg gcg tac 816 Ser Val Thr Gly GlyArg Leu Asp Thr Arg Glu Leu Asp Ala Ala Tyr 260 265 270 tgg tac cgc aacatg tcg agc acg gtc cgg ttc gag ccc gcc gcc cgg 864 Trp Tyr Arg Asn MetSer Ser Thr Val Arg Phe Glu Pro Ala Ala Arg 275 280 285 ctg ctt ctg cagcag ggg ccc aag acg ttc gtc gag atg agc ccg cac 912 Leu Leu Leu Gln GlnGly Pro Lys Thr Phe Val Glu Met Ser Pro His 290 295 300 ccg gtg ctg accatg ggc ctc cag gag ctc gcc ccg gac ctg ggc gac 960 Pro Val Leu Thr MetGly Leu Gln Glu Leu Ala Pro Asp Leu Gly Asp 305 310 315 320 acc acc ggcacc gcc gac acc gtg atc atg ggc acg ctg cgc cgc ggc 1008 Thr Thr Gly ThrAla Asp Thr Val Ile Met Gly Thr Leu Arg Arg Gly 325 330 335 cag ggc accctg gac cac ttc ctg acg tct ctc gcc caa cta cgg ggg 1056 Gln Gly Thr LeuAsp His Phe Leu Thr Ser Leu Ala Gln Leu Arg Gly 340 345 350 cat ggt gagacg tcg gcg acc acc gtc ctc tcg gca cgc ctg acc gcg 1104 His Gly Glu ThrSer Ala Thr Thr Val Leu Ser Ala Arg Leu Thr Ala 355 360 365 ctg tcc cccacg cag cag cag tcg ctg ctc ctg gac ctg gtg cgc gcc 1152 Leu Ser Pro ThrGln Gln Gln Ser Leu Leu Leu Asp Leu Val Arg Ala 370 375 380 cac acc atggcg gtg ctg aac gac gac gga aac gag cgc acc gcg tcg 1200 His Thr Met AlaVal Leu Asn Asp Asp Gly Asn Glu Arg Thr Ala Ser 385 390 395 400 gat gccggc cca tcg gcg agt ttc gcc cac ctc ggc ttc gac tcc gtc 1248 Asp Ala GlyPro Ser Ala Ser Phe Ala His Leu Gly Phe Asp Ser Val 405 410 415 atg ggtgtc gaa ctg cgc aac cgc ctc agc aag gcc acg ggc ctg cgg 1296 Met Gly ValGlu Leu Arg Asn Arg Leu Ser Lys Ala Thr Gly Leu Arg 420 425 430 ttg cccgtg acg ctc atc ttc gac cac acc acg ccg gcc gcg gtc gcc 1344 Leu Pro ValThr Leu Ile Phe Asp His Thr Thr Pro Ala Ala Val Ala 435 440 445 gcg cgcctt cgg acc gcg gcg ctc ggc cac ctc gac gag gac acc gcg 1392 Ala Arg LeuArg Thr Ala Ala Leu Gly His Leu Asp Glu Asp Thr Ala 450 455 460 ccc gtaccg gac tca ccc agc ggc cac gga ggc acg gca gcg gcg gac 1440 Pro Val ProAsp Ser Pro Ser Gly His Gly Gly Thr Ala Ala Ala Asp 465 470 475 480 gacccg atc gcc atc atc ggc atg gca tgc cgt ttc ccg ggc gga gtc 1488 Asp ProIle Ala Ile Ile Gly Met Ala Cys Arg Phe Pro Gly Gly Val 485 490 495 cggtcc ccg aag gac ctg tgg gag ctg gcc gcc tcg ggc gga gac gcc 1536 Arg SerPro Lys Asp Leu Trp Glu Leu Ala Ala Ser Gly Gly Asp Ala 500 505 510 atcggg ccg ttc ccc acc gac cgc gga tgg ccc acg gaa cag cgt cac 1584 Ile GlyPro Phe Pro Thr Asp Arg Gly Trp Pro Thr Glu Gln Arg His 515 520 525 gcccag gac ccc acg cag ccc ggc acg ttc tat ccg cag gga ggc ggg 1632 Ala GlnAsp Pro Thr Gln Pro Gly Thr Phe Tyr Pro Gln Gly Gly Gly 530 535 540 ttcctt cac gac gcg gcg cac ttc gac gcc ggc ttc ttc gga atc agt 1680 Phe LeuHis Asp Ala Ala His Phe Asp Ala Gly Phe Phe Gly Ile Ser 545 550 555 560cca cgt gag gca ctg gcg atg gat ccg cag cag cgg ctg ctg ctg gag 1728 ProArg Glu Ala Leu Ala Met Asp Pro Gln Gln Arg Leu Leu Leu Glu 565 570 575acg tcc tgg gag gcg ttc gag cgg gcg gga atc gat ccg ctg tcg gta 1776 ThrSer Trp Glu Ala Phe Glu Arg Ala Gly Ile Asp Pro Leu Ser Val 580 585 590cgc ggg tcc cgt acg ggc gtc ttc gcg ggc gcc ctc tcc ttc gac tac 1824 ArgGly Ser Arg Thr Gly Val Phe Ala Gly Ala Leu Ser Phe Asp Tyr 595 600 605ggc ccg cgt atg gac acc gcg tcg tcg gag ggc gcc gcg gac gtg gag 1872 GlyPro Arg Met Asp Thr Ala Ser Ser Glu Gly Ala Ala Asp Val Glu 610 615 620ggc cac atc ctc acc ggt acc acg ggc agc gtc ctg tcg ggc cgt atc 1920 GlyHis Ile Leu Thr Gly Thr Thr Gly Ser Val Leu Ser Gly Arg Ile 625 630 635640 gcc tac agc ttc ggg ctg gaa ggg ccg gcg atc acc gtg gac acg ggg 1968Ala Tyr Ser Phe Gly Leu Glu Gly Pro Ala Ile Thr Val Asp Thr Gly 645 650655 ggc tcg gca tcg ctc gtg acg ctg cat ctg gcg tgc cag tcg ctg cgg 2016Gly Ser Ala Ser Leu Val Thr Leu His Leu Ala Cys Gln Ser Leu Arg 660 665670 tcg ggt gag tgc acg ctc gcg ctg gcc ggc ggc gtc tcg gtc atg tcc 2064Ser Gly Glu Cys Thr Leu Ala Leu Ala Gly Gly Val Ser Val Met Ser 675 680685 acc ctc ggc atg ttc atc gag ttc tcc cgg cag cgc ggg ctg tcg gtg 2112Thr Leu Gly Met Phe Ile Glu Phe Ser Arg Gln Arg Gly Leu Ser Val 690 695700 gac ggc agg tgc aag gcg tac tcg gct gca gcc gac ggc acc ggc tgg 2160Asp Gly Arg Cys Lys Ala Tyr Ser Ala Ala Ala Asp Gly Thr Gly Trp 705 710715 720 ggc gag ggc gtc ggg atg ctg ttg gtg gag cgg ttg tcg gat gcg gtg2208 Gly Glu Gly Val Gly Met Leu Leu Val Glu Arg Leu Ser Asp Ala Val 725730 735 cgg ctg ggg cat cgg gtg ctg gcg gtg gta cgc ggc agt gcg gtc aac2256 Arg Leu Gly His Arg Val Leu Ala Val Val Arg Gly Ser Ala Val Asn 740745 750 cag gac ggt gcg tcg aat ggg ctg acg gcg ccg aac ggt ccg gct cag2304 Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro Ala Gln 755760 765 gag cgg gtg atc cgg cag gcg ttg gcg aac gcg ggg ttg tcc gtg gcg2352 Glu Arg Val Ile Arg Gln Ala Leu Ala Asn Ala Gly Leu Ser Val Ala 770775 780 gat gtg gat gtg gtg gag ggg cac ggg acg ggc acg acg ctg ggt gat2400 Asp Val Asp Val Val Glu Gly His Gly Thr Gly Thr Thr Leu Gly Asp 785790 795 800 ccg atc gag gca cag gcg ttg ctc gcc acg tac ggg cag cgg gccggt 2448 Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Arg Ala Gly805 810 815 gac agg ccg ctg tgg ctg ggg tct ctg aag tcc aac atc ggg cacacc 2496 Asp Arg Pro Leu Trp Leu Gly Ser Leu Lys Ser Asn Ile Gly His Thr820 825 830 atg gct gcc gcg ggt gtg ggt ggg gtc atc aag atg gtg atg gcgttg 2544 Met Ala Ala Ala Gly Val Gly Gly Val Ile Lys Met Val Met Ala Leu835 840 845 cgg gag ggg gtg ttg ccg cgg acg ttg cat gtg gat aag ccg tcgccg 2592 Arg Glu Gly Val Leu Pro Arg Thr Leu His Val Asp Lys Pro Ser Pro850 855 860 cag gtg gac tgg tcc gcg ggg gcg gtg cgg ctg ctg acg gag gcggtg 2640 Gln Val Asp Trp Ser Ala Gly Ala Val Arg Leu Leu Thr Glu Ala Val865 870 875 880 ccg tgg ccg ggg gac gcg gca ggg cgg ttg cgg cgg gcg ggagtg tcg 2688 Pro Trp Pro Gly Asp Ala Ala Gly Arg Leu Arg Arg Ala Gly ValSer 885 890 895 tcg ttc ggg atc ggc ggc acg aat gcg cat gtg att ttg gaggag gcg 2736 Ser Phe Gly Ile Gly Gly Thr Asn Ala His Val Ile Leu Glu GluAla 900 905 910 ccg gcg gcg ggg ggc tgt gtt gcc ggg ggt ggg gtg ttg gagggt gct 2784 Pro Ala Ala Gly Gly Cys Val Ala Gly Gly Gly Val Leu Glu GlyAla 915 920 925 ccg ggt ctt gcc att tcg gtg gct gag tcg gtg gcc gct ccagtg gct 2832 Pro Gly Leu Ala Ile Ser Val Ala Glu Ser Val Ala Ala Pro ValAla 930 935 940 gtg tct gcg ccg gtg gct gag tcg gtg ccg gtg ccg gtg ccggtg ccg 2880 Val Ser Ala Pro Val Ala Glu Ser Val Pro Val Pro Val Pro ValPro 945 950 955 960 gtt cct gtg ccg gtg tcg gct agg tct gag gct ggg ttgcgg gcg cag 2928 Val Pro Val Pro Val Ser Ala Arg Ser Glu Ala Gly Leu ArgAla Gln 965 970 975 gcg gag gcg ttg cgt cag tac gtg gca gtc cgg ccg gacgtt tcg ctt 2976 Ala Glu Ala Leu Arg Gln Tyr Val Ala Val Arg Pro Asp ValSer Leu 980 985 990 gcc gat gtg ggt gcg ggt ctg gcc tgt ggg cgg gct gtgctg gag cat 3024 Ala Asp Val Gly Ala Gly Leu Ala Cys Gly Arg Ala Val LeuGlu His 995 1000 1005 cgt gcg gtc gtc ctg gcc gcg gac cgt gag gag ctggtg caa ggg ttg 3072 Arg Ala Val Val Leu Ala Ala Asp Arg Glu Glu Leu ValGln Gly Leu 1010 1015 1020 ggg gcg ctg gcg gcg ggt gag ccg gat cgg cgggtg acc acg ggt cat 3120 Gly Ala Leu Ala Ala Gly Glu Pro Asp Arg Arg ValThr Thr Gly His 1025 1030 1035 1040 gcg ccg ggt ggt gac cgg ggc ggt gtcgtc ttc gtg ttt ccc gga cag 3168 Ala Pro Gly Gly Asp Arg Gly Gly Val ValPhe Val Phe Pro Gly Gln 1045 1050 1055 ggt ggg cag tgg gcc ggg atg ggtgtg cgt ctg ctc gcc tcc tct ccg 3216 Gly Gly Gln Trp Ala Gly Met Gly ValArg Leu Leu Ala Ser Ser Pro 1060 1065 1070 gtg ttc gcc cgg cgg atg caggcg tgc gag gag gct ctg gcg ccg tgg 3264 Val Phe Ala Arg Arg Met Gln AlaCys Glu Glu Ala Leu Ala Pro Trp 1075 1080 1085 gtg gac tgg tct gtg gtggac atc ctg cgc cgg gac gcg ggg gat gcg 3312 Val Asp Trp Ser Val Val AspIle Leu Arg Arg Asp Ala Gly Asp Ala 1090 1095 1100 gtg tgg gag cgg gccgat gtg gtc cag cct gtg ctg ttc agc gtc atg 3360 Val Trp Glu Arg Ala AspVal Val Gln Pro Val Leu Phe Ser Val Met 1105 1110 1115 1120 gtg tct ttggct gct ctg tgg cgt tcc tac ggt atc gaa ccc gac gcg 3408 Val Ser Leu AlaAla Leu Trp Arg Ser Tyr Gly Ile Glu Pro Asp Ala 1125 1130 1135 gtc cttggc cat tcc cag ggc gag atc gcg gcc gcg cat gtg tgt ggg 3456 Val Leu GlyHis Ser Gln Gly Glu Ile Ala Ala Ala His Val Cys Gly 1140 1145 1150 gcgctg agc ctg aag gac gcg gcg aag act gtt gcg ctg cgc agc cgg 3504 Ala LeuSer Leu Lys Asp Ala Ala Lys Thr Val Ala Leu Arg Ser Arg 1155 1160 1165gcg ctg gcc gct gtg cgg ggc cgg ggc ggc atg gcc tca gtg ccg ctg 3552 AlaLeu Ala Ala Val Arg Gly Arg Gly Gly Met Ala Ser Val Pro Leu 1170 11751180 cct gcc cag gag gtg gag cag ctc att ggt gag cgg tgg gcg ggg cgg3600 Pro Ala Gln Glu Val Glu Gln Leu Ile Gly Glu Arg Trp Ala Gly Arg1185 1190 1195 1200 ttg tgg gtg gcg gcg gtc aac ggc ccc cgc tcc acc gccgtc tcg ggg 3648 Leu Trp Val Ala Ala Val Asn Gly Pro Arg Ser Thr Ala ValSer Gly 1205 1210 1215 gat gcc gag gcg gtg gac gag gtg ctg gcg tac tgtgcc ggc acc ggg 3696 Asp Ala Glu Ala Val Asp Glu Val Leu Ala Tyr Cys AlaGly Thr Gly 1220 1225 1230 gtg cgg gcc cgg cgg atc ccg gtc gac tat gcctcg cac tgc ccc cat 3744 Val Arg Ala Arg Arg Ile Pro Val Asp Tyr Ala SerHis Cys Pro His 1235 1240 1245 gtg cag ccc ctg cgg gag gag ttg ctg gagctg ctg ggg gac atc agc 3792 Val Gln Pro Leu Arg Glu Glu Leu Leu Glu LeuLeu Gly Asp Ile Ser 1250 1255 1260 ccg cag ccg tcc ggc gtg ccg ttc ttctcc acg gtg gag ggc acc tgg 3840 Pro Gln Pro Ser Gly Val Pro Phe Phe SerThr Val Glu Gly Thr Trp 1265 1270 1275 1280 ctg gac acc aca acc ctg gacgcc gcc tac tgg tac cgc aac ctg cac 3888 Leu Asp Thr Thr Thr Leu Asp AlaAla Tyr Trp Tyr Arg Asn Leu His 1285 1290 1295 cag ccg gtc cgt ttc agcgat gcc gtc cag gcc ctg gcg gat gac gga 3936 Gln Pro Val Arg Phe Ser AspAla Val Gln Ala Leu Ala Asp Asp Gly 1300 1305 1310 cac cgc gtc ttc gtcgaa gtc agc ccc cac ccc acc ctc gtc ccc gcc 3984 His Arg Val Phe Val GluVal Ser Pro His Pro Thr Leu Val Pro Ala 1315 1320 1325 atc gaa gac accacc gaa gac acc gcc gaa gac gtc acc gcg atc ggc 4032 Ile Glu Asp Thr ThrGlu Asp Thr Ala Glu Asp Val Thr Ala Ile Gly 1330 1335 1340 agc ctc cgccgc ggc gac aac gac acc cgc cgc ttc ctc acc gcc ctc 4080 Ser Leu Arg ArgGly Asp Asn Asp Thr Arg Arg Phe Leu Thr Ala Leu 1345 1350 1355 1360 gcccac acc cat acc acc ggc atc ggc aca ccc acc acc tgg cac cac 4128 Ala HisThr His Thr Thr Gly Ile Gly Thr Pro Thr Thr Trp His His 1365 1370 1375cac tac acc cac cac cac acc cac ccc cac ccc cac acg cac ctc gac 4176 HisTyr Thr His His His Thr His Pro His Pro His Thr His Leu Asp 1380 13851390 ctg ccc acc tac ccc ttc caa cac cag cac tac tgg ctc gag agc tca4224 Leu Pro Thr Tyr Pro Phe Gln His Gln His Tyr Trp Leu Glu Ser Ser1395 1400 1405 cag ccg ggt gcc gga tcc ggt tcg ggt gcc ggt gcc ggt tcgggt gcc 4272 Gln Pro Gly Ala Gly Ser Gly Ser Gly Ala Gly Ala Gly Ser GlyAla 1410 1415 1420 ggt tcc ggg cgg gca ggg act gcg ggc ggg acg gca gaggtg gag tcg 4320 Gly Ser Gly Arg Ala Gly Thr Ala Gly Gly Thr Ala Glu ValGlu Ser 1425 1430 1435 1440 cgg ttc tgg gac gcg gtg gcc cgc cag gac ctggaa acg gtc gcg acc 4368 Arg Phe Trp Asp Ala Val Ala Arg Gln Asp Leu GluThr Val Ala Thr 1445 1450 1455 aca ctc gcc gtg ccc ccc tcc gcc ggc ctggac acg gtg gtg ccc gca 4416 Thr Leu Ala Val Pro Pro Ser Ala Gly Leu AspThr Val Val Pro Ala 1460 1465 1470 ctc tcc gcc tgg cac cgc cac caa cacgac caa gcc cgc atc aac acc 4464 Leu Ser Ala Trp His Arg His Gln His AspGln Ala Arg Ile Asn Thr 1475 1480 1485 tgg acc tac cag gaa acc tgg aaaccc ctc acc ctc ccc acc acc cac 4512 Trp Thr Tyr Gln Glu Thr Trp Lys ProLeu Thr Leu Pro Thr Thr His 1490 1495 1500 caa ccc cac caa acc tgg ctcatc gcc atc ccc gaa acc cag acc cac 4560 Gln Pro His Gln Thr Trp Leu IleAla Ile Pro Glu Thr Gln Thr His 1505 1510 1515 1520 cac ccc cac atc accaac atc ctc acc aac ctc cac cac cac ggc atc 4608 His Pro His Ile Thr AsnIle Leu Thr Asn Leu His His His Gly Ile 1525 1530 1535 acc ccc atc cccctc acc ctc aac cac acc cac acc aac ccc caa cac 4656 Thr Pro Ile Pro LeuThr Leu Asn His Thr His Thr Asn Pro Gln His 1540 1545 1550 ctc cac cacacc ctc cac cac acc cga caa caa gcc caa aac cac acc 4704 Leu His His ThrLeu His His Thr Arg Gln Gln Ala Gln Asn His Thr 1555 1560 1565 acc ggagcc atc acc ggc ctg ctc tcc ctc ctc gcc ctc gac gaa aca 4752 Thr Gly AlaIle Thr Gly Leu Leu Ser Leu Leu Ala Leu Asp Glu Thr 1570 1575 1580 ccccac ccc cac cac ccc cac aca ccc acc ggc acc ctc ctc aac ctc 4800 Pro HisPro His His Pro His Thr Pro Thr Gly Thr Leu Leu Asn Leu 1585 1590 15951600 acc ctc acc caa acc cac acc caa acc cac cca cca acc ccc ctc tgg4848 Thr Leu Thr Gln Thr His Thr Gln Thr His Pro Pro Thr Pro Leu Trp1605 1610 1615 tac gcc acc acc aac gcc acc acc acc cac ccc aac gac cccctc aca 4896 Tyr Ala Thr Thr Asn Ala Thr Thr Thr His Pro Asn Asp Pro LeuThr 1620 1625 1630 cac ccc acc caa gcc caa acc tgg gga ctc gcc cgc accacc ctc ctc 4944 His Pro Thr Gln Ala Gln Thr Trp Gly Leu Ala Arg Thr ThrLeu Leu 1635 1640 1645 gaa cac ccc acc cac acc gcc gga atc atc gac ctcccc acc acc ccc 4992 Glu His Pro Thr His Thr Ala Gly Ile Ile Asp Leu ProThr Thr Pro 1650 1655 1660 acc ccc cac acc ctc cag cac ctc acc caa accctc acc caa ccc cac 5040 Thr Pro His Thr Leu Gln His Leu Thr Gln Thr LeuThr Gln Pro His 1665 1670 1675 1680 cac caa acc caa ctc gcc atc cgc accacc ggc acc cac acc cgc cgc 5088 His Gln Thr Gln Leu Ala Ile Arg Thr ThrGly Thr His Thr Arg Arg 1685 1690 1695 ctc acc ccc acc acc ctc acc cccaca cac caa cca ccc acc ccc acc 5136 Leu Thr Pro Thr Thr Leu Thr Pro ThrHis Gln Pro Pro Thr Pro Thr 1700 1705 1710 ccc cac gga acc acc ctc atcacc ggc gga acc ggc gcc ctc gcc acc 5184 Pro His Gly Thr Thr Leu Ile ThrGly Gly Thr Gly Ala Leu Ala Thr 1715 1720 1725 cac ctc acc cac cac ctcacc acc cac caa ccc acc caa cac ctc ctc 5232 His Leu Thr His His Leu ThrThr His Gln Pro Thr Gln His Leu Leu 1730 1735 1740 ctc acc agc cga accggc ccc cac acc ccc cac gca caa cac ctc acc 5280 Leu Thr Ser Arg Thr GlyPro His Thr Pro His Ala Gln His Leu Thr 1745 1750 1755 1760 acc caa ctccaa caa aaa ggc atc cac ctc acc atc acc acc tgc gac 5328 Thr Gln Leu GlnGln Lys Gly Ile His Leu Thr Ile Thr Thr Cys Asp 1765 1770 1775 acc agcaac cca gac caa ctc caa caa ctc ctc aac acc atc ccc cca 5376 Thr Ser AsnPro Asp Gln Leu Gln Gln Leu Leu Asn Thr Ile Pro Pro 1780 1785 1790 caacac ccc ctc acc acc gtc atc cac acc gca ggc atc ctc gac gac 5424 Gln HisPro Leu Thr Thr Val Ile His Thr Ala Gly Ile Leu Asp Asp 1795 1800 1805gcc acc ctc acc aac ctc acc ccc acc caa ctc aac aac gtc ctc cgc 5472 AlaThr Leu Thr Asn Leu Thr Pro Thr Gln Leu Asn Asn Val Leu Arg 1810 18151820 gcc aaa gcc cac agc gcc cac ctc ctc cac caa ctc acc caa cac acc5520 Ala Lys Ala His Ser Ala His Leu Leu His Gln Leu Thr Gln His Thr1825 1830 1835 1840 ccc ctc acc gcc ttc gtc ctc tac tcc tcc gcc gcc gccacc ttc ggc 5568 Pro Leu Thr Ala Phe Val Leu Tyr Ser Ser Ala Ala Ala ThrPhe Gly 1845 1850 1855 gca ccc ggc caa gcc aac tac gcc gca gcc aac gcctac ctc gac gcc 5616 Ala Pro Gly Gln Ala Asn Tyr Ala Ala Ala Asn Ala TyrLeu Asp Ala 1860 1865 1870 ctc gcc cac cac cgc cac acc cac cac ctc cccgcc acc agc atc gcc 5664 Leu Ala His His Arg His Thr His His Leu Pro AlaThr Ser Ile Ala 1875 1880 1885 tgg ggc acc tgg caa gga aac gga ctc gctgat tcg gac aag gcc cgc 5712 Trp Gly Thr Trp Gln Gly Asn Gly Leu Ala AspSer Asp Lys Ala Arg 1890 1895 1900 gca tat ctc gac cgc cgc ggg ttt cgaccc atg tca ccc gag ttg gcc 5760 Ala Tyr Leu Asp Arg Arg Gly Phe Arg ProMet Ser Pro Glu Leu Ala 1905 1910 1915 1920 acg gca gcg gtc acg cag gcgatc gcg gac acc gaa cgg ccg tat gtc 5808 Thr Ala Ala Val Thr Gln Ala IleAla Asp Thr Glu Arg Pro Tyr Val 1925 1930 1935 gtc atc gcc gac atc gactgg agc aag atc gaa cac acc tct cag acc 5856 Val Ile Ala Asp Ile Asp TrpSer Lys Ile Glu His Thr Ser Gln Thr 1940 1945 1950 agc gac ctg gtg agcgcg gcc cgg gaa agg gag cca gct gtc cag cgc 5904 Ser Asp Leu Val Ser AlaAla Arg Glu Arg Glu Pro Ala Val Gln Arg 1955 1960 1965 ccc act cca ccggcg gag ttg cac aaa acg ctg gcc cat cag acg tcg 5952 Pro Thr Pro Pro AlaGlu Leu His Lys Thr Leu Ala His Gln Thr Ser 1970 1975 1980 gcc gac caacgg gcc gca ttg ctc gag ctc gta cga gac cat gtg gcg 6000 Ala Asp Gln ArgAla Ala Leu Leu Glu Leu Val Arg Asp His Val Ala 1985 1990 1995 2000 gcagtg ctc cgg cac gcg gac ccg aaa gcc atc gcg ccc gac cag tcg 6048 Ala ValLeu Arg His Ala Asp Pro Lys Ala Ile Ala Pro Asp Gln Ser 2005 2010 2015ttc cgt gca ctc ggc ttc gat tca ctc acg gcc gtc gag ttc cga aac 6096 PheArg Ala Leu Gly Phe Asp Ser Leu Thr Ala Val Glu Phe Arg Asn 2020 20252030 ctg ctg atc aag gca aca gga ctc cgc ctt cct gtc tcg ctg gtc ttc6144 Leu Leu Ile Lys Ala Thr Gly Leu Arg Leu Pro Val Ser Leu Val Phe2035 2040 2045 gac cac ccg acc cct gcc aaa ctc gcc gta cac ctg cag aaccaa ctg 6192 Asp His Pro Thr Pro Ala Lys Leu Ala Val His Leu Gln Asn GlnLeu 2050 2055 2060 cgg ggc aca gca gcg gag tcg gct cct tca gcg gca gccgtt acc gcc 6240 Arg Gly Thr Ala Ala Glu Ser Ala Pro Ser Ala Ala Ala ValThr Ala 2065 2070 2075 2080 gag gct tct gtc acc gag ccg atc gcc atc gttggc atg gcc tgt cgt 6288 Glu Ala Ser Val Thr Glu Pro Ile Ala Ile Val GlyMet Ala Cys Arg 2085 2090 2095 ttc ccc ggc gga gtg acc tcg gcg gac gacttc tgg gat ctg atc tcc 6336 Phe Pro Gly Gly Val Thr Ser Ala Asp Asp PheTrp Asp Leu Ile Ser 2100 2105 2110 tcc gag cag gac gcg atc ggc gga ttcccc acc gac cgc ggc tgg gac 6384 Ser Glu Gln Asp Ala Ile Gly Gly Phe ProThr Asp Arg Gly Trp Asp 2115 2120 2125 ctg gac acg ctc tac gac ccc gacccc gac cac ccc ggc acc tgc tac 6432 Leu Asp Thr Leu Tyr Asp Pro Asp ProAsp His Pro Gly Thr Cys Tyr 2130 2135 2140 acc cga aac ggc gga ttc ctctac gac gca ggc cac ttc gac gcc gaa 6480 Thr Arg Asn Gly Gly Phe Leu TyrAsp Ala Gly His Phe Asp Ala Glu 2145 2150 2155 2160 ttc ttc ggc atc agcccc cgc gaa gcc ctc gcc atg gac ccc cag caa 6528 Phe Phe Gly Ile Ser ProArg Glu Ala Leu Ala Met Asp Pro Gln Gln 2165 2170 2175 cga ctc ctc ctcgaa acc gcc tgg gaa acc atc gaa cac gcc ggc atc 6576 Arg Leu Leu Leu GluThr Ala Trp Glu Thr Ile Glu His Ala Gly Ile 2180 2185 2190 aac ccc cacacc ctc cac ggc acc ccc acc gga gtc ttc acc ggc acc 6624 Asn Pro His ThrLeu His Gly Thr Pro Thr Gly Val Phe Thr Gly Thr 2195 2200 2205 aac ggacag gac tac gca ctt cgc gtg cac aac gcg ggc cag tca acc 6672 Asn Gly GlnAsp Tyr Ala Leu Arg Val His Asn Ala Gly Gln Ser Thr 2210 2215 2220 gatggt ttc gca ctg acc gga acc gcc ggc agc gtc atc tcc ggt cgt 6720 Asp GlyPhe Ala Leu Thr Gly Thr Ala Gly Ser Val Ile Ser Gly Arg 2225 2230 22352240 atc tcg tac acg ttt ggt ttt gag ggt cct gcg gtg tcg gtg gac acg6768 Ile Ser Tyr Thr Phe Gly Phe Glu Gly Pro Ala Val Ser Val Asp Thr2245 2250 2255 gct tgt tcc tcg tcg ttg gtg gct ttg cat ctg gcc tgt caggcg ttg 6816 Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln AlaLeu 2260 2265 2270 cgt gcg ggt gag tgc tcg atg gcg ctt gcc ggg ggt gtgacg gtg atg 6864 Arg Ala Gly Glu Cys Ser Met Ala Leu Ala Gly Gly Val ThrVal Met 2275 2280 2285 tcg tct ccg ggt gcc ttc gtg gag ttt tcg cgg cagcgg ggt ctg gcc 6912 Ser Ser Pro Gly Ala Phe Val Glu Phe Ser Arg Gln ArgGly Leu Ala 2290 2295 2300 gcg gac ggg cat tgc aag gcg ttc tcg gcg gcggcg gac ggg acc ggc 6960 Ala Asp Gly His Cys Lys Ala Phe Ser Ala Ala AlaAsp Gly Thr Gly 2305 2310 2315 2320 tgg ggt gag ggt gtg ggg atg ctg ctggtg gag cgg ctc tcc gac gcc 7008 Trp Gly Glu Gly Val Gly Met Leu Leu ValGlu Arg Leu Ser Asp Ala 2325 2330 2335 cat cgc aac ggt cac cgt gtc ctggcc gtg gtg cgt ggc agt gcg gtc 7056 His Arg Asn Gly His Arg Val Leu AlaVal Val Arg Gly Ser Ala Val 2340 2345 2350 aac cag gac ggt gcg agc aacggt ctg acc gcg ccc aac ggg ccg tcc 7104 Asn Gln Asp Gly Ala Ser Asn GlyLeu Thr Ala Pro Asn Gly Pro Ser 2355 2360 2365 cag cag cgt gtc atc cgccag gcc ctc gcc aac gcc ggc ttg tcg gcc 7152 Gln Gln Arg Val Ile Arg GlnAla Leu Ala Asn Ala Gly Leu Ser Ala 2370 2375 2380 ggt gat gtc gac gcggtg gag gcc cac ggc acc ggc acc act ttg ggc 7200 Gly Asp Val Asp Ala ValGlu Ala His Gly Thr Gly Thr Thr Leu Gly 2385 2390 2395 2400 gac ccg atcgag gcc cag gcc ctc ctc gcg acc tac gga cag gac cgt 7248 Asp Pro Ile GluAla Gln Ala Leu Leu Ala Thr Tyr Gly Gln Asp Arg 2405 2410 2415 gcc ggcgag ggg ccg ctg tgg ctg ggc tcg gtc aag tcc aat gtc ggt 7296 Ala Gly GluGly Pro Leu Trp Leu Gly Ser Val Lys Ser Asn Val Gly 2420 2425 2430 cacaca cag gct gcc gcg ggc gtc gcc ggg gtg atc aag atg gtg atg 7344 His ThrGln Ala Ala Ala Gly Val Ala Gly Val Ile Lys Met Val Met 2435 2440 2445gcg ctg cgg cat ggt ctg ctg ccg cgg acg ttg cat gtg gat gag ccg 7392 AlaLeu Arg His Gly Leu Leu Pro Arg Thr Leu His Val Asp Glu Pro 2450 24552460 tcg ccg cat gtg gac tgg tcc gcg ggt gcg gtg cag ctg ctg acg gag7440 Ser Pro His Val Asp Trp Ser Ala Gly Ala Val Gln Leu Leu Thr Glu2465 2470 2475 2480 acg gtg ccc tgg ccc ggc ggg gag ggg cgg cta cgg cgggca gga gtg 7488 Thr Val Pro Trp Pro Gly Gly Glu Gly Arg Leu Arg Arg AlaGly Val 2485 2490 2495 tca tca ttc ggc gtc agc ggc acc aac gcc cac gtcatc ctc gaa gaa 7536 Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val IleLeu Glu Glu 2500 2505 2510 gca ccc gcc gac gac gtt ccg ggg gga cca cccgcc ggc gag ggt gac 7584 Ala Pro Ala Asp Asp Val Pro Gly Gly Pro Pro AlaGly Glu Gly Asp 2515 2520 2525 gcg ggc agc gac gat gag gct gct gcc ggcagt cct ggg gtg tgg ccg 7632 Ala Gly Ser Asp Asp Glu Ala Ala Ala Gly SerPro Gly Val Trp Pro 2530 2535 2540 tgg ctg gtg tcg gcc aag tcg cag ccggcc ctg cgc gcc cag gcc cag 7680 Trp Leu Val Ser Ala Lys Ser Gln Pro AlaLeu Arg Ala Gln Ala Gln 2545 2550 2555 2560 gcc ctg cac gcc cac ctc accgac cac ccc ggc ctc gac ctc gcg gat 7728 Ala Leu His Ala His Leu Thr AspHis Pro Gly Leu Asp Leu Ala Asp 2565 2570 2575 gtc gga tac acc ctc gcccac gcc cgc gcc gtg ttc gac cac cgc gcc 7776 Val Gly Tyr Thr Leu Ala HisAla Arg Ala Val Phe Asp His Arg Ala 2580 2585 2590 acc ctc atc gcc gcggac cgc gac acg ttc ctg caa gca ctc cag gca 7824 Thr Leu Ile Ala Ala AspArg Asp Thr Phe Leu Gln Ala Leu Gln Ala 2595 2600 2605 ctc gcc gca ggcgag ccc cac ccc gcc gtc atc cac agc agc gcc ccg 7872 Leu Ala Ala Gly GluPro His Pro Ala Val Ile His Ser Ser Ala Pro 2610 2615 2620 ggc ggg accggg acc ggg gag gcc gca gga aag acc gca ttc atc tgc 7920 Gly Gly Thr GlyThr Gly Glu Ala Ala Gly Lys Thr Ala Phe Ile Cys 2625 2630 2635 2640 tccgga cag ggc acc caa cgc ccc ggc atg gcc cac ggc ctc tac cac 7968 Ser GlyGln Gly Thr Gln Arg Pro Gly Met Ala His Gly Leu Tyr His 2645 2650 2655acc cac ccc gtc ttc gcc gcc gca ctc aac gac atc tgc acc cac ctc 8016 ThrHis Pro Val Phe Ala Ala Ala Leu Asn Asp Ile Cys Thr His Leu 2660 26652670 gac ccc cac ctc gac cac ccc ctc ctc ccc ctc ctc acc caa aac gac8064 Asp Pro His Leu Asp His Pro Leu Leu Pro Leu Leu Thr Gln Asn Asp2675 2680 2685 aac gac aac gag gac gcg gcc gca ctg ctc cag cag acc cgctac gcc 8112 Asn Asp Asn Glu Asp Ala Ala Ala Leu Leu Gln Gln Thr Arg TyrAla 2690 2695 2700 cag ccc gcc ctc ttc gcc ttc cag gtc gcc ctc cac cgcctc ctc acc 8160 Gln Pro Ala Leu Phe Ala Phe Gln Val Ala Leu His Arg LeuLeu Thr 2705 2710 2715 2720 gac ggc tac cac atc acc ccc cac tac tac gccgga cac tcc ctc ggc 8208 Asp Gly Tyr His Ile Thr Pro His Tyr Tyr Ala GlyHis Ser Leu Gly 2725 2730 2735 gaa atc acc gcc gcc cac ctc gcc ggc atcctc acc ctc acc gac gcc 8256 Glu Ile Thr Ala Ala His Leu Ala Gly Ile LeuThr Leu Thr Asp Ala 2740 2745 2750 acc acc ctc atc acc caa cgc gcc accctc atg caa acc atg ccc ccc 8304 Thr Thr Leu Ile Thr Gln Arg Ala Thr LeuMet Gln Thr Met Pro Pro 2755 2760 2765 ggc acc atg acc acc ctc cac accacc ccc cac cac atc acc cac cac 8352 Gly Thr Met Thr Thr Leu His Thr ThrPro His His Ile Thr His His 2770 2775 2780 ctc acc gcc cac gaa aac gacctc gcc atc gcc gcc atc aac acc ccc 8400 Leu Thr Ala His Glu Asn Asp LeuAla Ile Ala Ala Ile Asn Thr Pro 2785 2790 2795 2800 acc tcc ctc gtc atcagc ggc acc ccc cac acc gtc caa cac atc acc 8448 Thr Ser Leu Val Ile SerGly Thr Pro His Thr Val Gln His Ile Thr 2805 2810 2815 acc ctc tgc caacaa caa ggc atc aaa acc aaa acc ctc ccc acc aac 8496 Thr Leu Cys Gln GlnGln Gly Ile Lys Thr Lys Thr Leu Pro Thr Asn 2820 2825 2830 cac gcc ttccac tcc ccc cac acc aac ccc atc ctc aac caa ctc cac 8544 His Ala Phe HisSer Pro His Thr Asn Pro Ile Leu Asn Gln Leu His 2835 2840 2845 cag cacacc caa acc ctc acc tac cac cca ccc cac acc ccc ctc atc 8592 Gln His ThrGln Thr Leu Thr Tyr His Pro Pro His Thr Pro Leu Ile 2850 2855 2860 accgcc aac acc cca ccc gac caa ctc ctc acc ccc cac tac tgg acc 8640 Thr AlaAsn Thr Pro Pro Asp Gln Leu Leu Thr Pro His Tyr Trp Thr 2865 2870 28752880 caa caa gcc cgc aac acc gtc gac tac gcc acc acc acc caa acc ctc8688 Gln Gln Ala Arg Asn Thr Val Asp Tyr Ala Thr Thr Thr Gln Thr Leu2885 2890 2895 cac caa cac ggc gtc acc acc tac atc gaa ctc gga ccc gacaac acc 8736 His Gln His Gly Val Thr Thr Tyr Ile Glu Leu Gly Pro Asp AsnThr 2900 2905 2910 ctc acc acc ctc acc cac cac aac ctc ccc aac ccc cccacc acc acc 8784 Leu Thr Thr Leu Thr His His Asn Leu Pro Asn Pro Pro ThrThr Thr 2915 2920 2925 ctc acc ctc acc cac ccc cac cac cac ccc caa acccac ctc ctc acc 8832 Leu Thr Leu Thr His Pro His His His Pro Gln Thr HisLeu Leu Thr 2930 2935 2940 aac ctc gcc aaa acc acc acc acc tgg cac ccccac cac tac acc cac 8880 Asn Leu Ala Lys Thr Thr Thr Thr Trp His Pro HisHis Tyr Thr His 2945 2950 2955 2960 cac gac aac caa ccc cac acc cac acccac ctc gac ctc ccc acc tac 8928 His Asp Asn Gln Pro His Thr His Thr HisLeu Asp Leu Pro Thr Tyr 2965 2970 2975 ccc ttc caa cac cac cac tac tggctc gaa agc aca cag ccc ggt gcc 8976 Pro Phe Gln His His His Tyr Trp LeuGlu Ser Thr Gln Pro Gly Ala 2980 2985 2990 ggc aac gtg tca gca gcc ggactc gac ccc acc gaa cac ccc cta ctc 9024 Gly Asn Val Ser Ala Ala Gly LeuAsp Pro Thr Glu His Pro Leu Leu 2995 3000 3005 ggc gcc aca ttg gaa ctggcg act gac ggt gga gcg ctt ctt gca ggg 9072 Gly Ala Thr Leu Glu Leu AlaThr Asp Gly Gly Ala Leu Leu Ala Gly 3010 3015 3020 cgc ttg tct ttg aggtcg cat ccg tgg ctg gct gac cat gcc gtc ggc 9120 Arg Leu Ser Leu Arg SerHis Pro Trp Leu Ala Asp His Ala Val Gly 3025 3030 3035 3040 ggc acg gtgctg ctg tcg ggc gcc acc ttc ctc gaa ctc gcc ctt cat 9168 Gly Thr Val LeuLeu Ser Gly Ala Thr Phe Leu Glu Leu Ala Leu His 3045 3050 3055 gcg ggcaca tac gtg ggc tgc gac cga gtg gat gag ctg acg ctg cat 9216 Ala Gly ThrTyr Val Gly Cys Asp Arg Val Asp Glu Leu Thr Leu His 3060 3065 3070 gcgccg ctg gtg gtt cct gtg gat ggg ggt gtg agt gtg cag gtt ggg 9264 Ala ProLeu Val Val Pro Val Asp Gly Gly Val Ser Val Gln Val Gly 3075 3080 3085gtt gcg gct gcg gat ggg gag ggg cgg cgt ttg gtg agt gtg tat gcg 9312 ValAla Ala Ala Asp Gly Glu Gly Arg Arg Leu Val Ser Val Tyr Ala 3090 30953100 cgg ggt ggg agt gct tgt ggt ggg ggt ggt gcg tcg ggt ggg gtg tgg9360 Arg Gly Gly Ser Ala Cys Gly Gly Gly Gly Ala Ser Gly Gly Val Trp3105 3110 3115 3120 acg tgt cat gcc tcg ggg gtg ctg gtt gag gct gct gctggt ggt gtg 9408 Thr Cys His Ala Ser Gly Val Leu Val Glu Ala Ala Ala GlyGly Val 3125 3130 3135 gtg gtg gat ggt ctg gcg ggg gtg tgg ccg ccg cggggt gcg gtg gcg 9456 Val Val Asp Gly Leu Ala Gly Val Trp Pro Pro Arg GlyAla Val Ala 3140 3145 3150 gtg gat gtc gat ggt gtc cgt gac cgt ttg gctggg gct ggt tgt gtt 9504 Val Asp Val Asp Gly Val Arg Asp Arg Leu Ala GlyAla Gly Cys Val 3155 3160 3165 ttg ggg ccg gtg ttt tcg ggg ctg cgt gcggtg tgg cgt gat ggg ggg 9552 Leu Gly Pro Val Phe Ser Gly Leu Arg Ala ValTrp Arg Asp Gly Gly 3170 3175 3180 gat ttg ctg gct gag gtg tgt ctg ccggag gag gcg tgg ggt gat gcg 9600 Asp Leu Leu Ala Glu Val Cys Leu Pro GluGlu Ala Trp Gly Asp Ala 3185 3190 3195 3200 gct ggt ttt ggg ctg cat ccggcg ttg ctg gat ggt gtg gtc cag ccg 9648 Ala Gly Phe Gly Leu His Pro AlaLeu Leu Asp Gly Val Val Gln Pro 3205 3210 3215 ttg tcg gtg ttg ctt ccgggt ggg acg ggg ttt ggg gag ggg gcg ggg 9696 Leu Ser Val Leu Leu Pro GlyGly Thr Gly Phe Gly Glu Gly Ala Gly 3220 3225 3230 ttc ggg gag ggt gttcgg gtg ccg gct gtg tgg ggt ggt gtg tcg ctt 9744 Phe Gly Glu Gly Val ArgVal Pro Ala Val Trp Gly Gly Val Ser Leu 3235 3240 3245 cac cgg gcg ggtgtg acc ggt gtg cgg gtg cgt gtg tcg gct gtc ggg 9792 His Arg Ala Gly ValThr Gly Val Arg Val Arg Val Ser Ala Val Gly 3250 3255 3260 cgg ggc ggcggg cgt gag gcg gtg tcg gtc gtg gtc ggg gat gag gcg 9840 Arg Gly Gly GlyArg Glu Ala Val Ser Val Val Val Gly Asp Glu Ala 3265 3270 3275 3280 ggtgtg ccg gtg gcg tcg gtc gat cgt ctt gag ttg cgg cct gtg gat 9888 Gly ValPro Val Ala Ser Val Asp Arg Leu Glu Leu Arg Pro Val Asp 3285 3290 3295atg ggt cag ttg cgt gct gtc tcg gtt tcg gcg ggg cgg cgg ggt tcg 9936 MetGly Gln Leu Arg Ala Val Ser Val Ser Ala Gly Arg Arg Gly Ser 3300 33053310 ctg tat gcg gtg cag tgg gct gag gtg ggt cct gtg ccg gtg tgt ggg9984 Leu Tyr Ala Val Gln Trp Ala Glu Val Gly Pro Val Pro Val Cys Gly3315 3320 3325 cag gcg tgg gcg tgg cac gag gac gtg ggt gag agc ggt ggtggg cct 10032 Gln Ala Trp Ala Trp His Glu Asp Val Gly Glu Ser Gly GlyGly Pro 3330 3335 3340 gtg ccg ggg gtg gtg gtg ttg cgg tgc ccg gat gccggt gcc ggt ggc 10080 Val Pro Gly Val Val Val Leu Arg Cys Pro Asp AlaGly Ala Gly Gly 3345 3350 3355 3360 ggt ggc ggt ggc ggt ggt ggc ggt ggtgtg ggt gag gtt gtt ggt ggg 10128 Gly Gly Gly Gly Gly Gly Gly Gly GlyVal Gly Glu Val Val Gly Gly 3365 3370 3375 gtg ttg ggt gtg gtg cag gggtgg ctg ggg ctg gag cgg ttt gcg ggt 10176 Val Leu Gly Val Val Gln GlyTrp Leu Gly Leu Glu Arg Phe Ala Gly 3380 3385 3390 tcg cgg ctg gtg gtggtg acc cgg ggt gcg gtg gtg gcc ggc ccg gag 10224 Ser Arg Leu Val ValVal Thr Arg Gly Ala Val Val Ala Gly Pro Glu 3395 3400 3405 gac ggc ccggtg gat gtg gtg ggt gcg tcg gtg tgg ggg ctg gtg cgt 10272 Asp Gly ProVal Asp Val Val Gly Ala Ser Val Trp Gly Leu Val Arg 3410 3415 3420 tcggcg cag gct gag cat ccg gac cgg ttt gtc ctc ctc gac ctc gac 10320 SerAla Gln Ala Glu His Pro Asp Arg Phe Val Leu Leu Asp Leu Asp 3425 34303435 3440 acc gac acc ggc acc gac ctc gac acc ggt gct ggt gct ggt tggggc 10368 Thr Asp Thr Gly Thr Asp Leu Asp Thr Gly Ala Gly Ala Gly TrpGly 3445 3450 3455 gtg gat ggt ggg cgt gtg gcg gcg gtg gtg gcg tgt ggtgag ccg cag 10416 Val Asp Gly Gly Arg Val Ala Ala Val Val Ala Cys GlyGlu Pro Gln 3460 3465 3470 ttg gcg gtg cgt ggg gag cgg ttg ctg gcc gcacgc ctg aaa cga ctt 10464 Leu Ala Val Arg Gly Glu Arg Leu Leu Ala AlaArg Leu Lys Arg Leu 3475 3480 3485 gag tca tcc ggt gat gtt cca gcc cagcgg tcc ggt gac aca cga gcc 10512 Glu Ser Ser Gly Asp Val Pro Ala GlnArg Ser Gly Asp Thr Arg Ala 3490 3495 3500 cgg cgg tcc gac gtg cct gcccag cgc tcc ggt ggc gtg cct gct cgg 10560 Arg Arg Ser Asp Val Pro AlaGln Arg Ser Gly Gly Val Pro Ala Arg 3505 3510 3515 3520 cgg tcg gtt gatgta tcg ggt cgg gag gtg ttg ccg tgg ttg tcg ggt 10608 Arg Ser Val AspVal Ser Gly Arg Glu Val Leu Pro Trp Leu Ser Gly 3525 3530 3535 ggg tcggtg ttg gtg acg ggt ggg acg ggt gtg ctg ggt gcg gcg gtg 10656 Gly SerVal Leu Val Thr Gly Gly Thr Gly Val Leu Gly Ala Ala Val 3540 3545 3550gcg cgg cat ctg gct ggt gtg tgt ggg gtg cgg gat ctg ctg ttg gtg 10704Ala Arg His Leu Ala Gly Val Cys Gly Val Arg Asp Leu Leu Leu Val 35553560 3565 agc cgg cgt ggt ccg gat gct ccg ggt gcg gag ggt ctg cgg gcggag 10752 Ser Arg Arg Gly Pro Asp Ala Pro Gly Ala Glu Gly Leu Arg AlaGlu 3570 3575 3580 ctg gcc gcg ttg ggg gcg gag gtg cgg att gtt gcg tgtgat gtg ggg 10800 Leu Ala Ala Leu Gly Ala Glu Val Arg Ile Val Ala CysAsp Val Gly 3585 3590 3595 3600 gag cgg cgg gag gtg gtc cgg ctg ctg gagggt gtt cct gcc ggg tgt 10848 Glu Arg Arg Glu Val Val Arg Leu Leu GluGly Val Pro Ala Gly Cys 3605 3610 3615 ccg ctg acg ggt gtc gtg cat gcggct ggt gtg ctg gac gat gcg acg 10896 Pro Leu Thr Gly Val Val His AlaAla Gly Val Leu Asp Asp Ala Thr 3620 3625 3630 atc gcc tct ctc acg cccgag cgg ctg ggc acg gtg ttc gcg gcc aag 10944 Ile Ala Ser Leu Thr ProGlu Arg Leu Gly Thr Val Phe Ala Ala Lys 3635 3640 3645 gtg gat gcc gctctt ttg ctg gat gag ctg acg cgg ggt atg gag ctg 10992 Val Asp Ala AlaLeu Leu Leu Asp Glu Leu Thr Arg Gly Met Glu Leu 3650 3655 3660 tcg gcgttc gtg ctg ttc tcc tcg gcc gcg ggg atc ctg ggg tcg gcc 11040 Ser AlaPhe Val Leu Phe Ser Ser Ala Ala Gly Ile Leu Gly Ser Ala 3665 3670 36753680 ggg cag ggc aac tac gcc gcg gcc aat gcc gct ctg gac gcg ctg gcg11088 Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Ala Leu Asp Ala Leu Ala3685 3690 3695 tac cgg cgg cgg gcg gcg ggt ctg ccg ggg gtg tcg ctg gcgtgg ggg 11136 Tyr Arg Arg Arg Ala Ala Gly Leu Pro Gly Val Ser Leu AlaTrp Gly 3700 3705 3710 ctg tgg gaa gag gcc agc ggg atg acc ggg cac ctggcc ggc acc gac 11184 Leu Trp Glu Glu Ala Ser Gly Met Thr Gly His LeuAla Gly Thr Asp 3715 3720 3725 cac cgg cgc atc atc cgt tcc ggt ctg catccc atg tcg acc ccg gac 11232 His Arg Arg Ile Ile Arg Ser Gly Leu HisPro Met Ser Thr Pro Asp 3730 3735 3740 gca ctg gcc ctc ttc gat gcg gccctg gct ctg gac cgg ccg gtc ctg 11280 Ala Leu Ala Leu Phe Asp Ala AlaLeu Ala Leu Asp Arg Pro Val Leu 3745 3750 3755 3760 ctg ccc gcc gac ctgcgt ccc gcc ccg ccc ctg ccg ccc ctg ctg cag 11328 Leu Pro Ala Asp LeuArg Pro Ala Pro Pro Leu Pro Pro Leu Leu Gln 3765 3770 3775 gac ctc ctgccc gcc acc cgc cgc cgc acc acc cgc acc acc act acc 11376 Asp Leu LeuPro Ala Thr Arg Arg Arg Thr Thr Arg Thr Thr Thr Thr 3780 3785 3790 ggtggt gcg gac aac ggc gcc cag ctg cac gcc cgg ctg gcc ggc cag 11424 GlyGly Ala Asp Asn Gly Ala Gln Leu His Ala Arg Leu Ala Gly Gln 3795 38003805 aca cac gaa caa cag cac acc acc ctc ctc gcc ctg gtc cgc tcc cac11472 Thr His Glu Gln Gln His Thr Thr Leu Leu Ala Leu Val Arg Ser His3810 3815 3820 atc gcc acc gtc ctg ggc cac acc acc ccc gac acc atc cccccc gac 11520 Ile Ala Thr Val Leu Gly His Thr Thr Pro Asp Thr Ile ProPro Asp 3825 3830 3835 3840 cgc gcg ttc cgc gac ctc ggc ttc gac tcc ctcacc gcc gtc gaa cta 11568 Arg Ala Phe Arg Asp Leu Gly Phe Asp Ser LeuThr Ala Val Glu Leu 3845 3850 3855 cgc aac cgg ctc tcc cgc acc acc ggactc cgc ctc ccc acc acc ctc 11616 Arg Asn Arg Leu Ser Arg Thr Thr GlyLeu Arg Leu Pro Thr Thr Leu 3860 3865 3870 gcc ttc gac cac ccc aac cccacc acc ctc acc cac cac ctc cac aca 11664 Ala Phe Asp His Pro Asn ProThr Thr Leu Thr His His Leu His Thr 3875 3880 3885 caa ctc cag cca caaccg gac aac gct gtc gcc ccc gtg ttg gcg gag 11712 Gln Leu Gln Pro GlnPro Asp Asn Ala Val Ala Pro Val Leu Ala Glu 3890 3895 3900 ctc gac aaactc gaa tcc gcc ctc tcc gcc ctc gac aaa acc gac agc 11760 Leu Asp LysLeu Glu Ser Ala Leu Ser Ala Leu Asp Lys Thr Asp Ser 3905 3910 3915 3920gcc agc gaa aga gtc acc ctg cgg ctg aag tca ctc atg ttg agg tgg 11808Ala Ser Glu Arg Val Thr Leu Arg Leu Lys Ser Leu Met Leu Arg Trp 39253930 3935 aac gca ccc cag cat ccg aca gcc gaa agc gct gat gac gac gagaag 11856 Asn Ala Pro Gln His Pro Thr Ala Glu Ser Ala Asp Asp Asp GluLys 3940 3945 3950 ttc aca tcg gca aca gag gct gag att ttc aaa ttc attgac aac gac 11904 Phe Thr Ser Ala Thr Glu Ala Glu Ile Phe Lys Phe IleAsp Asn Asp 3955 3960 3965 ctc ggc ctg tcc 11916 Leu Gly Leu Ser 4 3972PRT Streptomyces avermitilis 4 Val Gln Arg Met Asp Gly Gly Glu Glu ProArg Pro Ala Ala Gly Glu 1 5 10 15 Val Leu Gly Val Ala Asp Glu Ala AspGly Gly Val Val Phe Val Phe 20 25 30 Pro Gly Gln Gly Pro Gln Trp Pro GlyMet Gly Arg Glu Leu Leu Asp 35 40 45 Ala Ser Asp Val Phe Arg Glu Ser ValArg Ala Cys Glu Ala Ala Phe 50 55 60 Ala Pro Tyr Val Asp Trp Ser Val GluGln Val Leu Arg Asp Ser Pro 65 70 75 80 Asp Ala Pro Gly Leu Asp Arg ValAsp Val Val Gln Pro Thr Leu Phe 85 90 95 Ala Val Met Ile Ser Leu Ala AlaLeu Trp Arg Ser Gln Gly Val Glu 100 105 110 Pro Cys Ala Val Leu Gly HisSer Leu Gly Glu Ile Ala Ala Ala His 115 120 125 Val Ser Gly Gly Leu SerLeu Ala Asp Ala Ala Arg Val Val Thr Leu 130 135 140 Trp Ser Gln Ala GlnThr Thr Leu Ala Gly Thr Gly Ala Leu Val Ser 145 150 155 160 Val Ala AlaThr Pro Asp Glu Leu Leu Pro Arg Ile Ala Pro Trp Thr 165 170 175 Glu AspAsn Pro Ala Arg Leu Ala Val Ala Ala Val Asn Gly Pro Arg 180 185 190 SerThr Val Val Ser Gly Ala Arg Glu Ala Val Ala Asp Leu Val Ala 195 200 205Asp Leu Thr Ala Ala Gln Val Arg Thr Arg Met Ile Pro Val Asp Val 210 215220 Pro Ala His Ser Pro Leu Met Tyr Ala Ile Glu Glu Arg Val Val Ser 225230 235 240 Gly Leu Leu Pro Ile Thr Pro Arg Pro Ser Arg Ile Pro Phe HisSer 245 250 255 Ser Val Thr Gly Gly Arg Leu Asp Thr Arg Glu Leu Asp AlaAla Tyr 260 265 270 Trp Tyr Arg Asn Met Ser Ser Thr Val Arg Phe Glu ProAla Ala Arg 275 280 285 Leu Leu Leu Gln Gln Gly Pro Lys Thr Phe Val GluMet Ser Pro His 290 295 300 Pro Val Leu Thr Met Gly Leu Gln Glu Leu AlaPro Asp Leu Gly Asp 305 310 315 320 Thr Thr Gly Thr Ala Asp Thr Val IleMet Gly Thr Leu Arg Arg Gly 325 330 335 Gln Gly Thr Leu Asp His Phe LeuThr Ser Leu Ala Gln Leu Arg Gly 340 345 350 His Gly Glu Thr Ser Ala ThrThr Val Leu Ser Ala Arg Leu Thr Ala 355 360 365 Leu Ser Pro Thr Gln GlnGln Ser Leu Leu Leu Asp Leu Val Arg Ala 370 375 380 His Thr Met Ala ValLeu Asn Asp Asp Gly Asn Glu Arg Thr Ala Ser 385 390 395 400 Asp Ala GlyPro Ser Ala Ser Phe Ala His Leu Gly Phe Asp Ser Val 405 410 415 Met GlyVal Glu Leu Arg Asn Arg Leu Ser Lys Ala Thr Gly Leu Arg 420 425 430 LeuPro Val Thr Leu Ile Phe Asp His Thr Thr Pro Ala Ala Val Ala 435 440 445Ala Arg Leu Arg Thr Ala Ala Leu Gly His Leu Asp Glu Asp Thr Ala 450 455460 Pro Val Pro Asp Ser Pro Ser Gly His Gly Gly Thr Ala Ala Ala Asp 465470 475 480 Asp Pro Ile Ala Ile Ile Gly Met Ala Cys Arg Phe Pro Gly GlyVal 485 490 495 Arg Ser Pro Lys Asp Leu Trp Glu Leu Ala Ala Ser Gly GlyAsp Ala 500 505 510 Ile Gly Pro Phe Pro Thr Asp Arg Gly Trp Pro Thr GluGln Arg His 515 520 525 Ala Gln Asp Pro Thr Gln Pro Gly Thr Phe Tyr ProGln Gly Gly Gly 530 535 540 Phe Leu His Asp Ala Ala His Phe Asp Ala GlyPhe Phe Gly Ile Ser 545 550 555 560 Pro Arg Glu Ala Leu Ala Met Asp ProGln Gln Arg Leu Leu Leu Glu 565 570 575 Thr Ser Trp Glu Ala Phe Glu ArgAla Gly Ile Asp Pro Leu Ser Val 580 585 590 Arg Gly Ser Arg Thr Gly ValPhe Ala Gly Ala Leu Ser Phe Asp Tyr 595 600 605 Gly Pro Arg Met Asp ThrAla Ser Ser Glu Gly Ala Ala Asp Val Glu 610 615 620 Gly His Ile Leu ThrGly Thr Thr Gly Ser Val Leu Ser Gly Arg Ile 625 630 635 640 Ala Tyr SerPhe Gly Leu Glu Gly Pro Ala Ile Thr Val Asp Thr Gly 645 650 655 Cys SerAla Ser Leu Val Thr Leu His Leu Ala Cys Gln Ser Leu Arg 660 665 670 SerGly Glu Cys Thr Leu Ala Leu Ala Gly Gly Val Ser Val Met Ser 675 680 685Thr Leu Gly Met Phe Ile Glu Phe Ser Arg Gln Arg Gly Leu Ser Val 690 695700 Asp Gly Arg Cys Lys Ala Tyr Ser Ala Ala Ala Asp Gly Thr Gly Trp 705710 715 720 Gly Glu Gly Val Gly Met Leu Leu Val Glu Arg Leu Ser Asp AlaVal 725 730 735 Arg Leu Gly His Arg Val Leu Ala Val Val Arg Gly Ser AlaVal Asn 740 745 750 Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn GlyPro Ala Gln 755 760 765 Glu Arg Val Ile Arg Gln Ala Leu Ala Asn Ala GlyLeu Ser Val Ala 770 775 780 Asp Val Asp Val Val Glu Gly His Gly Thr GlyThr Thr Leu Gly Asp 785 790 795 800 Pro Ile Glu Ala Gln Ala Leu Leu AlaThr Tyr Gly Gln Arg Ala Gly 805 810 815 Asp Arg Pro Leu Trp Leu Gly SerLeu Lys Ser Asn Ile Gly His Thr 820 825 830 Met Ala Ala Ala Gly Val GlyGly Val Ile Lys Met Val Met Ala Leu 835 840 845 Arg Glu Gly Val Leu ProArg Thr Leu His Val Asp Lys Pro Ser Pro 850 855 860 Gln Val Asp Trp SerAla Gly Ala Val Arg Leu Leu Thr Glu Ala Val 865 870 875 880 Pro Trp ProGly Asp Ala Ala Gly Arg Leu Arg Arg Ala Gly Val Ser 885 890 895 Ser PheGly Ile Gly Gly Thr Asn Ala His Val Ile Leu Glu Glu Ala 900 905 910 ProAla Ala Gly Gly Cys Val Ala Gly Gly Gly Val Leu Glu Gly Ala 915 920 925Pro Gly Leu Ala Ile Ser Val Ala Glu Ser Val Ala Ala Pro Val Ala 930 935940 Val Ser Ala Pro Val Ala Glu Ser Val Pro Val Pro Val Pro Val Pro 945950 955 960 Val Pro Val Pro Val Ser Ala Arg Ser Glu Ala Gly Leu Arg AlaGln 965 970 975 Ala Glu Ala Leu Arg Gln Tyr Val Ala Val Arg Pro Asp ValSer Leu 980 985 990 Ala Asp Val Gly Ala Gly Leu Ala Cys Gly Arg Ala ValLeu Glu His 995 1000 1005 Arg Ala Val Val Leu Ala Ala Asp Arg Glu GluLeu Val Gln Gly Leu 1010 1015 1020 Gly Ala Leu Ala Ala Gly Glu Pro AspArg Arg Val Thr Thr Gly His 1025 1030 1035 1040 Ala Pro Gly Gly Asp ArgGly Gly Val Val Phe Val Phe Pro Gly Gln 1045 1050 1055 Gly Gly Gln TrpAla Gly Met Gly Val Arg Leu Leu Ala Ser Ser Pro 1060 1065 1070 Val PheAla Arg Arg Met Gln Ala Cys Glu Glu Ala Leu Ala Pro Trp 1075 1080 1085Val Asp Trp Ser Val Val Asp Ile Leu Arg Arg Asp Ala Gly Asp Ala 10901095 1100 Val Trp Glu Arg Ala Asp Val Val Gln Pro Val Leu Phe Ser ValMet 1105 1110 1115 1120 Val Ser Leu Ala Ala Leu Trp Arg Ser Tyr Gly IleGlu Pro Asp Ala 1125 1130 1135 Val Leu Gly His Ser Gln Gly Glu Ile AlaAla Ala His Val Cys Gly 1140 1145 1150 Ala Leu Ser Leu Lys Asp Ala AlaLys Thr Val Ala Leu Arg Ser Arg 1155 1160 1165 Ala Leu Ala Ala Val ArgGly Arg Gly Gly Met Ala Ser Val Pro Leu 1170 1175 1180 Pro Ala Gln GluVal Glu Gln Leu Ile Gly Glu Arg Trp Ala Gly Arg 1185 1190 1195 1200 LeuTrp Val Ala Ala Val Asn Gly Pro Arg Ser Thr Ala Val Ser Gly 1205 12101215 Asp Ala Glu Ala Val Asp Glu Val Leu Ala Tyr Cys Ala Gly Thr Gly1220 1225 1230 Val Arg Ala Arg Arg Ile Pro Val Asp Tyr Ala Ser His CysPro His 1235 1240 1245 Val Gln Pro Leu Arg Glu Glu Leu Leu Glu Leu LeuGly Asp Ile Ser 1250 1255 1260 Pro Gln Pro Ser Gly Val Pro Phe Phe SerThr Val Glu Gly Thr Trp 1265 1270 1275 1280 Leu Asp Thr Thr Thr Leu AspAla Ala Tyr Trp Tyr Arg Asn Leu His 1285 1290 1295 Gln Pro Val Arg PheSer Asp Ala Val Gln Ala Leu Ala Asp Asp Gly 1300 1305 1310 His Arg ValPhe Val Glu Val Ser Pro His Pro Thr Leu Val Pro Ala 1315 1320 1325 IleGlu Asp Thr Thr Glu Asp Thr Ala Glu Asp Val Thr Ala Ile Gly 1330 13351340 Ser Leu Arg Arg Gly Asp Asn Asp Thr Arg Arg Phe Leu Thr Ala Leu1345 1350 1355 1360 Ala His Thr His Thr Thr Gly Ile Gly Thr Pro Thr ThrTrp His His 1365 1370 1375 His Tyr Thr His His His Thr His Pro His ProHis Thr His Leu Asp 1380 1385 1390 Leu Pro Thr Tyr Pro Phe Gln His GlnHis Tyr Trp Leu Glu Ser Ser 1395 1400 1405 Gln Pro Gly Ala Gly Ser GlySer Gly Ala Gly Ala Gly Ser Gly Ala 1410 1415 1420 Gly Ser Gly Arg AlaGly Thr Ala Gly Gly Thr Ala Glu Val Glu Ser 1425 1430 1435 1440 Arg PheTrp Asp Ala Val Ala Arg Gln Asp Leu Glu Thr Val Ala Thr 1445 1450 1455Thr Leu Ala Val Pro Pro Ser Ala Gly Leu Asp Thr Val Val Pro Ala 14601465 1470 Leu Ser Ala Trp His Arg His Gln His Asp Gln Ala Arg Ile AsnThr 1475 1480 1485 Trp Thr Tyr Gln Glu Thr Trp Lys Pro Leu Thr Leu ProThr Thr His 1490 1495 1500 Gln Pro His Gln Thr Trp Leu Ile Ala Ile ProGlu Thr Gln Thr His 1505 1510 1515 1520 His Pro His Ile Thr Asn Ile LeuThr Asn Leu His His His Gly Ile 1525 1530 1535 Thr Pro Ile Pro Leu ThrLeu Asn His Thr His Thr Asn Pro Gln His 1540 1545 1550 Leu His His ThrLeu His His Thr Arg Gln Gln Ala Gln Asn His Thr 1555 1560 1565 Thr GlyAla Ile Thr Gly Leu Leu Ser Leu Leu Ala Leu Asp Glu Thr 1570 1575 1580Pro His Pro His His Pro His Thr Pro Thr Gly Thr Leu Leu Asn Leu 15851590 1595 1600 Thr Leu Thr Gln Thr His Thr Gln Thr His Pro Pro Thr ProLeu Trp 1605 1610 1615 Tyr Ala Thr Thr Asn Ala Thr Thr Thr His Pro AsnAsp Pro Leu Thr 1620 1625 1630 His Pro Thr Gln Ala Gln Thr Trp Gly LeuAla Arg Thr Thr Leu Leu 1635 1640 1645 Glu His Pro Thr His Thr Ala GlyIle Ile Asp Leu Pro Thr Thr Pro 1650 1655 1660 Thr Pro His Thr Leu GlnHis Leu Thr Gln Thr Leu Thr Gln Pro His 1665 1670 1675 1680 His Gln ThrGln Leu Ala Ile Arg Thr Thr Gly Thr His Thr Arg Arg 1685 1690 1695 LeuThr Pro Thr Thr Leu Thr Pro Thr His Gln Pro Pro Thr Pro Thr 1700 17051710 Pro His Gly Thr Thr Leu Ile Thr Gly Gly Thr Gly Ala Leu Ala Thr1715 1720 1725 His Leu Thr His His Leu Thr Thr His Gln Pro Thr Gln HisLeu Leu 1730 1735 1740 Leu Thr Ser Arg Thr Gly Pro His Thr Pro His AlaGln His Leu Thr 1745 1750 1755 1760 Thr Gln Leu Gln Gln Lys Gly Ile HisLeu Thr Ile Thr Thr Cys Asp 1765 1770 1775 Thr Ser Asn Pro Asp Gln LeuGln Gln Leu Leu Asn Thr Ile Pro Pro 1780 1785 1790 Gln His Pro Leu ThrThr Val Ile His Thr Ala Gly Ile Leu Asp Asp 1795 1800 1805 Ala Thr LeuThr Asn Leu Thr Pro Thr Gln Leu Asn Asn Val Leu Arg 1810 1815 1820 AlaLys Ala His Ser Ala His Leu Leu His Gln Leu Thr Gln His Thr 1825 18301835 1840 Pro Leu Thr Ala Phe Val Leu Tyr Ser Ser Ala Ala Ala Thr PheGly 1845 1850 1855 Ala Pro Gly Gln Ala Asn Tyr Ala Ala Ala Asn Ala TyrLeu Asp Ala 1860 1865 1870 Leu Ala His His Arg His Thr His His Leu ProAla Thr Ser Ile Ala 1875 1880 1885 Trp Gly Thr Trp Gln Gly Asn Gly LeuAla Asp Ser Asp Lys Ala Arg 1890 1895 1900 Ala Tyr Leu Asp Arg Arg GlyPhe Arg Pro Met Ser Pro Glu Leu Ala 1905 1910 1915 1920 Thr Ala Ala ValThr Gln Ala Ile Ala Asp Thr Glu Arg Pro Tyr Val 1925 1930 1935 Val IleAla Asp Ile Asp Trp Ser Lys Ile Glu His Thr Ser Gln Thr 1940 1945 1950Ser Asp Leu Val Ser Ala Ala Arg Glu Arg Glu Pro Ala Val Gln Arg 19551960 1965 Pro Thr Pro Pro Ala Glu Leu His Lys Thr Leu Ala His Gln ThrSer 1970 1975 1980 Ala Asp Gln Arg Ala Ala Leu Leu Glu Leu Val Arg AspHis Val Ala 1985 1990 1995 2000 Ala Val Leu Arg His Ala Asp Pro Lys AlaIle Ala Pro Asp Gln Ser 2005 2010 2015 Phe Arg Ala Leu Gly Phe Asp SerLeu Thr Ala Val Glu Phe Arg Asn 2020 2025 2030 Leu Leu Ile Lys Ala ThrGly Leu Arg Leu Pro Val Ser Leu Val Phe 2035 2040 2045 Asp His Pro ThrPro Ala Lys Leu Ala Val His Leu Gln Asn Gln Leu 2050 2055 2060 Arg GlyThr Ala Ala Glu Ser Ala Pro Ser Ala Ala Ala Val Thr Ala 2065 2070 20752080 Glu Ala Ser Val Thr Glu Pro Ile Ala Ile Val Gly Met Ala Cys Arg2085 2090 2095 Phe Pro Gly Gly Val Thr Ser Ala Asp Asp Phe Trp Asp LeuIle Ser 2100 2105 2110 Ser Glu Gln Asp Ala Ile Gly Gly Phe Pro Thr AspArg Gly Trp Asp 2115 2120 2125 Leu Asp Thr Leu Tyr Asp Pro Asp Pro AspHis Pro Gly Thr Cys Tyr 2130 2135 2140 Thr Arg Asn Gly Gly Phe Leu TyrAsp Ala Gly His Phe Asp Ala Glu 2145 2150 2155 2160 Phe Phe Gly Ile SerPro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln 2165 2170 2175 Arg Leu LeuLeu Glu Thr Ala Trp Glu Thr Ile Glu His Ala Gly Ile 2180 2185 2190 AsnPro His Thr Leu His Gly Thr Pro Thr Gly Val Phe Thr Gly Thr 2195 22002205 Asn Gly Gln Asp Tyr Ala Leu Arg Val His Asn Ala Gly Gln Ser Thr2210 2215 2220 Asp Gly Phe Ala Leu Thr Gly Thr Ala Gly Ser Val Ile SerGly Arg 2225 2230 2235 2240 Ile Ser Tyr Thr Phe Gly Phe Glu Gly Pro AlaVal Ser Val Asp Thr 2245 2250 2255 Ala Cys Ser Ser Ser Leu Val Ala LeuHis Leu Ala Cys Gln Ala Leu 2260 2265 2270 Arg Ala Gly Glu Cys Ser MetAla Leu Ala Gly Gly Val Thr Val Met 2275 2280 2285 Ser Ser Pro Gly AlaPhe Val Glu Phe Ser Arg Gln Arg Gly Leu Ala 2290 2295 2300 Ala Asp GlyHis Cys Lys Ala Phe Ser Ala Ala Ala Asp Gly Thr Gly 2305 2310 2315 2320Trp Gly Glu Gly Val Gly Met Leu Leu Val Glu Arg Leu Ser Asp Ala 23252330 2335 His Arg Asn Gly His Arg Val Leu Ala Val Val Arg Gly Ser AlaVal 2340 2345 2350 Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro AsnGly Pro Ser 2355 2360 2365 Gln Gln Arg Val Ile Arg Gln Ala Leu Ala AsnAla Gly Leu Ser Ala 2370 2375 2380 Gly Asp Val Asp Ala Val Glu Ala HisGly Thr Gly Thr Thr Leu Gly 2385 2390 2395 2400 Asp Pro Ile Glu Ala GlnAla Leu Leu Ala Thr Tyr Gly Gln Asp Arg 2405 2410 2415 Ala Gly Glu GlyPro Leu Trp Leu Gly Ser Val Lys Ser Asn Val Gly 2420 2425 2430 His ThrGln Ala Ala Ala Gly Val Ala Gly Val Ile Lys Met Val Met 2435 2440 2445Ala Leu Arg His Gly Leu Leu Pro Arg Thr Leu His Val Asp Glu Pro 24502455 2460 Ser Pro His Val Asp Trp Ser Ala Gly Ala Val Gln Leu Leu ThrGlu 2465 2470 2475 2480 Thr Val Pro Trp Pro Gly Gly Glu Gly Arg Leu ArgArg Ala Gly Val 2485 2490 2495 Ser Ser Phe Gly Val Ser Gly Thr Asn AlaHis Val Ile Leu Glu Glu 2500 2505 2510 Ala Pro Ala Asp Asp Val Pro GlyGly Pro Pro Ala Gly Glu Gly Asp 2515 2520 2525 Ala Gly Ser Asp Asp GluAla Ala Ala Gly Ser Pro Gly Val Trp Pro 2530 2535 2540 Trp Leu Val SerAla Lys Ser Gln Pro Ala Leu Arg Ala Gln Ala Gln 2545 2550 2555 2560 AlaLeu His Ala His Leu Thr Asp His Pro Gly Leu Asp Leu Ala Asp 2565 25702575 Val Gly Tyr Thr Leu Ala His Ala Arg Ala Val Phe Asp His Arg Ala2580 2585 2590 Thr Leu Ile Ala Ala Asp Arg Asp Thr Phe Leu Gln Ala LeuGln Ala 2595 2600 2605 Leu Ala Ala Gly Glu Pro His Pro Ala Val Ile HisSer Ser Ala Pro 2610 2615 2620 Gly Gly Thr Gly Thr Gly Glu Ala Ala GlyLys Thr Ala Phe Ile Cys 2625 2630 2635 2640 Ser Gly Gln Gly Thr Gln ArgPro Gly Met Ala His Gly Leu Tyr His 2645 2650 2655 Thr His Pro Val PheAla Ala Ala Leu Asn Asp Ile Cys Thr His Leu 2660 2665 2670 Asp Pro HisLeu Asp His Pro Leu Leu Pro Leu Leu Thr Gln Asn Asp 2675 2680 2685 AsnAsp Asn Glu Asp Ala Ala Ala Leu Leu Gln Gln Thr Arg Tyr Ala 2690 26952700 Gln Pro Ala Leu Phe Ala Phe Gln Val Ala Leu His Arg Leu Leu Thr2705 2710 2715 2720 Asp Gly Tyr His Ile Thr Pro His Tyr Tyr Ala Gly HisSer Leu Gly 2725 2730 2735 Glu Ile Thr Ala Ala His Leu Ala Gly Ile LeuThr Leu Thr Asp Ala 2740 2745 2750 Thr Thr Leu Ile Thr Gln Arg Ala ThrLeu Met Gln Thr Met Pro Pro 2755 2760 2765 Gly Thr Met Thr Thr Leu HisThr Thr Pro His His Ile Thr His His 2770 2775 2780 Leu Thr Ala His GluAsn Asp Leu Ala Ile Ala Ala Ile Asn Thr Pro 2785 2790 2795 2800 Thr SerLeu Val Ile Ser Gly Thr Pro His Thr Val Gln His Ile Thr 2805 2810 2815Thr Leu Cys Gln Gln Gln Gly Ile Lys Thr Lys Thr Leu Pro Thr Asn 28202825 2830 His Ala Phe His Ser Pro His Thr Asn Pro Ile Leu Asn Gln LeuHis 2835 2840 2845 Gln His Thr Gln Thr Leu Thr Tyr His Pro Pro His ThrPro Leu Ile 2850 2855 2860 Thr Ala Asn Thr Pro Pro Asp Gln Leu Leu ThrPro His Tyr Trp Thr 2865 2870 2875 2880 Gln Gln Ala Arg Asn Thr Val AspTyr Ala Thr Thr Thr Gln Thr Leu 2885 2890 2895 His Gln His Gly Val ThrThr Tyr Ile Glu Leu Gly Pro Asp Asn Thr 2900 2905 2910 Leu Thr Thr LeuThr His His Asn Leu Pro Asn Pro Pro Thr Thr Thr 2915 2920 2925 Leu ThrLeu Thr His Pro His His His Pro Gln Thr His Leu Leu Thr 2930 2935 2940Asn Leu Ala Lys Thr Thr Thr Thr Trp His Pro His His Tyr Thr His 29452950 2955 2960 His Asp Asn Gln Pro His Thr His Thr His Leu Asp Leu ProThr Tyr 2965 2970 2975 Pro Phe Gln His His His Tyr Trp Leu Glu Ser ThrGln Pro Gly Ala 2980 2985 2990 Gly Asn Val Ser Ala Ala Gly Leu Asp ProThr Glu His Pro Leu Leu 2995 3000 3005 Gly Ala Thr Leu Glu Leu Ala ThrAsp Gly Gly Ala Leu Leu Ala Gly 3010 3015 3020 Arg Leu Ser Leu Arg SerHis Pro Trp Leu Ala Asp His Ala Val Gly 3025 3030 3035 3040 Gly Thr ValLeu Leu Ser Gly Ala Thr Phe Leu Glu Leu Ala Leu His 3045 3050 3055 AlaGly Thr Tyr Val Gly Cys Asp Arg Val Asp Glu Leu Thr Leu His 3060 30653070 Ala Pro Leu Val Val Pro Val Asp Gly Gly Val Ser Val Gln Val Gly3075 3080 3085 Val Ala Ala Ala Asp Gly Glu Gly Arg Arg Leu Val Ser ValTyr Ala 3090 3095 3100 Arg Gly Gly Ser Ala Cys Gly Gly Gly Gly Ala SerGly Gly Val Trp 3105 3110 3115 3120 Thr Cys His Ala Ser Gly Val Leu ValGlu Ala Ala Ala Gly Gly Val 3125 3130 3135 Val Val Asp Gly Leu Ala GlyVal Trp Pro Pro Arg Gly Ala Val Ala 3140 3145 3150 Val Asp Val Asp GlyVal Arg Asp Arg Leu Ala Gly Ala Gly Cys Val 3155 3160 3165 Leu Gly ProVal Phe Ser Gly Leu Arg Ala Val Trp Arg Asp Gly Gly 3170 3175 3180 AspLeu Leu Ala Glu Val Cys Leu Pro Glu Glu Ala Trp Gly Asp Ala 3185 31903195 3200 Ala Gly Phe Gly Leu His Pro Ala Leu Leu Asp Gly Val Val GlnPro 3205 3210 3215 Leu Ser Val Leu Leu Pro Gly Gly Thr Gly Phe Gly GluGly Ala Gly 3220 3225 3230 Phe Gly Glu Gly Val Arg Val Pro Ala Val TrpGly Gly Val Ser Leu 3235 3240 3245 His Arg Ala Gly Val Thr Gly Val ArgVal Arg Val Ser Ala Val Gly 3250 3255 3260 Arg Gly Gly Gly Arg Glu AlaVal Ser Val Val Val Gly Asp Glu Ala 3265 3270 3275 3280 Gly Val Pro ValAla Ser Val Asp Arg Leu Glu Leu Arg Pro Val Asp 3285 3290 3295 Met GlyGln Leu Arg Ala Val Ser Val Ser Ala Gly Arg Arg Gly Ser 3300 3305 3310Leu Tyr Ala Val Gln Trp Ala Glu Val Gly Pro Val Pro Val Cys Gly 33153320 3325 Gln Ala Trp Ala Trp His Glu Asp Val Gly Glu Ser Gly Gly GlyPro 3330 3335 3340 Val Pro Gly Val Val Val Leu Arg Cys Pro Asp Ala GlyAla Gly Gly 3345 3350 3355 3360 Gly Gly Gly Gly Gly Gly Gly Gly Gly ValGly Glu Val Val Gly Gly 3365 3370 3375 Val Leu Gly Val Val Gln Gly TrpLeu Gly Leu Glu Arg Phe Ala Gly 3380 3385 3390 Ser Arg Leu Val Val ValThr Arg Gly Ala Val Val Ala Gly Pro Glu 3395 3400 3405 Asp Gly Pro ValAsp Val Val Gly Ala Ser Val Trp Gly Leu Val Arg 3410 3415 3420 Ser AlaGln Ala Glu His Pro Asp Arg Phe Val Leu Leu Asp Leu Asp 3425 3430 34353440 Thr Asp Thr Gly Thr Asp Leu Asp Thr Gly Ala Gly Ala Gly Trp Gly3445 3450 3455 Val Asp Gly Gly Arg Val Ala Ala Val Val Ala Cys Gly GluPro Gln 3460 3465 3470 Leu Ala Val Arg Gly Glu Arg Leu Leu Ala Ala ArgLeu Lys Arg Leu 3475 3480 3485 Glu Ser Ser Gly Asp Val Pro Ala Gln ArgSer Gly Asp Thr Arg Ala 3490 3495 3500 Arg Arg Ser Asp Val Pro Ala GlnArg Ser Gly Gly Val Pro Ala Arg 3505 3510 3515 3520 Arg Ser Val Asp ValSer Gly Arg Glu Val Leu Pro Trp Leu Ser Gly 3525 3530 3535 Gly Ser ValLeu Val Thr Gly Gly Thr Gly Val Leu Gly Ala Ala Val 3540 3545 3550 AlaArg His Leu Ala Gly Val Cys Gly Val Arg Asp Leu Leu Leu Val 3555 35603565 Ser Arg Arg Gly Pro Asp Ala Pro Gly Ala Glu Gly Leu Arg Ala Glu3570 3575 3580 Leu Ala Ala Leu Gly Ala Glu Val Arg Ile Val Ala Cys AspVal Gly 3585 3590 3595 3600 Glu Arg Arg Glu Val Val Arg Leu Leu Glu GlyVal Pro Ala Gly Cys 3605 3610 3615 Pro Leu Thr Gly Val Val His Ala AlaGly Val Leu Asp Asp Ala Thr 3620 3625 3630 Ile Ala Ser Leu Thr Pro GluArg Leu Gly Thr Val Phe Ala Ala Lys 3635 3640 3645 Val Asp Ala Ala LeuLeu Leu Asp Glu Leu Thr Arg Gly Met Glu Leu 3650 3655 3660 Ser Ala PheVal Leu Phe Ser Ser Ala Ala Gly Ile Leu Gly Ser Ala 3665 3670 3675 3680Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Ala Leu Asp Ala Leu Ala 36853690 3695 Tyr Arg Arg Arg Ala Ala Gly Leu Pro Gly Val Ser Leu Ala TrpGly 3700 3705 3710 Leu Trp Glu Glu Ala Ser Gly Met Thr Gly His Leu AlaGly Thr Asp 3715 3720 3725 His Arg Arg Ile Ile Arg Ser Gly Leu His ProMet Ser Thr Pro Asp 3730 3735 3740 Ala Leu Ala Leu Phe Asp Ala Ala LeuAla Leu Asp Arg Pro Val Leu 3745 3750 3755 3760 Leu Pro Ala Asp Leu ArgPro Ala Pro Pro Leu Pro Pro Leu Leu Gln 3765 3770 3775 Asp Leu Leu ProAla Thr Arg Arg Arg Thr Thr Arg Thr Thr Thr Thr 3780 3785 3790 Gly GlyAla Asp Asn Gly Ala Gln Leu His Ala Arg Leu Ala Gly Gln 3795 3800 3805Thr His Glu Gln Gln His Thr Thr Leu Leu Ala Leu Val Arg Ser His 38103815 3820 Ile Ala Thr Val Leu Gly His Thr Thr Pro Asp Thr Ile Pro ProAsp 3825 3830 3835 3840 Arg Ala Phe Arg Asp Leu Gly Phe Asp Ser Leu ThrAla Val Glu Leu 3845 3850 3855 Arg Asn Arg Leu Ser Arg Thr Thr Gly LeuArg Leu Pro Thr Thr Leu 3860 3865 3870 Ala Phe Asp His Pro Asn Pro ThrThr Leu Thr His His Leu His Thr 3875 3880 3885 Gln Leu Gln Pro Gln ProAsp Asn Ala Val Ala Pro Val Leu Ala Glu 3890 3895 3900 Leu Asp Lys LeuGlu Ser Ala Leu Ser Ala Leu Asp Lys Thr Asp Ser 3905 3910 3915 3920 AlaSer Glu Arg Val Thr Leu Arg Leu Lys Ser Leu Met Leu Arg Trp 3925 39303935 Asn Ala Pro Gln His Pro Thr Ala Glu Ser Ala Asp Asp Asp Glu Lys3940 3945 3950 Phe Thr Ser Ala Thr Glu Ala Glu Ile Phe Lys Phe Ile AspAsn Asp 3955 3960 3965 Leu Gly Leu Ser 3970 5 6239 PRT Streptomycesavermitilis 5 Met Gln Leu Ala Asn Glu Ala Lys Leu Leu Glu Tyr Leu LysArg Val 1 5 10 15 Thr Ala Asp Leu Asp Arg Thr Arg Arg Arg Leu Tyr GluVal Val Glu 20 25 30 Arg Glu Gln Glu Pro Ile Ala Ile Val Gly Met Ala CysArg Tyr Pro 35 40 45 Gly Gly Ala Thr Ser Pro Thr Arg Leu Trp His Leu ValLys Ser Gln 50 55 60 Thr Asp Ala Ile Gly Glu Phe Pro Thr Asp Arg Gly TrpAsn Leu Glu 65 70 75 80 Gln Leu Tyr Asp Pro Asp Pro Asp Arg Ser Gly ThrSer Tyr Thr Arg 85 90 95 Ser Gly Gly Phe Leu Tyr Asp Ala Gly Asp Phe AspAla Ala Phe Phe 100 105 110 Glu Leu Ser Pro Arg Glu Ala Leu Ala Met AspPro Gln Gln Arg Leu 115 120 125 Leu Leu Glu Thr Thr Trp Glu Thr Phe GluGln Gly Gly Ile Asp Pro 130 135 140 Arg Ser Met Arg Gly Ser Arg Thr GlyVal Phe Val Gly Ile Asn Pro 145 150 155 160 Glu Asp Tyr Thr Thr Gly TyrThr His Gln Pro Ser Asn Ala Val Glu 165 170 175 Gly Tyr Leu Leu Thr GlySer Ala Ala Ser Ile Ala Ser Gly Arg Ile 180 185 190 Ser Tyr Asn Phe GlyLeu Glu Gly Pro Ala Ile Thr Ile Asp Thr Ala 195 200 205 Cys Ser Ser SerLeu Val Ala Leu His Leu Ala Cys Gln Ala Leu Arg 210 215 220 Ser Gly GluCys Thr Met Ala Leu Ala Gly Gly Ala Ser Val Met Ala 225 230 235 240 ThrPro Phe Val Phe Thr Glu Phe Ser Arg Gln Arg Gly Leu Ala Ala 245 250 255Asp Gly Arg Cys Lys Ala Phe Ser Ala Ala Ala Asp Gly Thr Gly Trp 260 265270 Ser Glu Gly Val Gly Met Leu Leu Val Glu Arg Leu Ser Asp Ala Arg 275280 285 Arg Asn Gly His Arg Val Leu Ala Val Val Arg Gly Ser Ala Val Asn290 295 300 Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly Arg SerGln 305 310 315 320 Val Lys Val Ile Arg Gln Ala Leu Ala Asn Ala His LeuSer Pro Ala 325 330 335 Asp Val Asp Ala Val Glu Ala His Gly Thr Gly ThrThr Leu Gly Asp 340 345 350 Pro Ile Glu Ala Gln Ala Leu Val Glu Ala TyrGly Gln Asp Arg Pro 355 360 365 Asn Gly Arg Pro Leu Trp Leu Gly Thr LeuLys Ser Asn Ile Gly His 370 375 380 Ser Met Ala Ala Ala Gly Val Gly GlyVal Ile Lys Met Val Met Ala 385 390 395 400 Leu Arg Asn Gly Leu Leu ProArg Thr Leu His Val Asp Glu Pro Ser 405 410 415 Pro His Val Asp Trp SerAla Gly Ala Val Gln Leu Leu Thr Glu Thr 420 425 430 Val Pro Trp Pro GlyGly Glu Gly Arg Leu Arg Arg Ala Gly Val Ser 435 440 445 Ser Phe Gly ValSer Gly Thr Asn Ala His Val Ile Leu Glu Glu Ala 450 455 460 Pro Ala HisAsn Ile Pro Ser Asp Thr Pro Ala Asp Asp Val Pro Gly 465 470 475 480 GluSer Ala Ala Asp Glu Asp Ala Gly Ser Gly Asp Glu Ala Ala Ala 485 490 495Gly Ser Pro Gly Val Trp Pro Trp Leu Val Ser Ala Lys Ser Gln Pro 500 505510 Ala Leu Arg Ala Gln Ala Gln Ala Leu His Ala His Leu Thr Asp His 515520 525 Pro Gly Leu Asp Leu Ala Asp Val Gly Tyr Thr Leu Ala His Ala Arg530 535 540 Ala Val Phe Asp His Arg Ala Thr Leu Ile Ala Ala Asp Arg AspThr 545 550 555 560 Phe Leu Gln Ala Leu Gln Ala Leu Ala Ala Gly Glu ProHis Pro Ala 565 570 575 Val Ile His Ser Ser Ala Pro Gly Gly Thr Gly ThrGly Glu Ala Ala 580 585 590 Gly Lys Thr Ala Phe Ile Cys Ser Gly Gln GlyThr Gln Arg Pro Gly 595 600 605 Met Ala His Gly Leu Tyr His Thr His ProVal Phe Ala Ala Ala Leu 610 615 620 Asn Asp Ile Cys Thr His Leu Asp ProHis Leu Asp His Pro Leu Leu 625 630 635 640 Pro Leu Leu Thr Gln Asp ProAsn Thr Gln Asp Thr Thr Thr Leu Glu 645 650 655 Glu Ala Ala Ala Leu LeuGln Gln Thr Arg Tyr Ala Gln Pro Ala Leu 660 665 670 Phe Ala Phe Gln ValAla Leu His Arg Leu Leu Thr Asp Gly Tyr His 675 680 685 Ile Thr Pro HisTyr Tyr Ala Gly His Ser Leu Gly Glu Ile Thr Ala 690 695 700 Ala His LeuAla Gly Ile Leu Thr Leu Thr Asp Ala Thr Thr Leu Ile 705 710 715 720 ThrGln Arg Ala Thr Leu Met Gln Thr Met Pro Pro Gly Thr Met Thr 725 730 735Thr Leu His Thr Thr Pro His His Ile Thr His His Leu Thr Ala His 740 745750 Glu Asn Asp Leu Ala Ile Ala Ala Ile Asn Thr Pro Thr Ser Leu Val 755760 765 Ile Ser Gly Thr Pro His Thr Val Gln His Ile Thr Thr Leu Cys Gln770 775 780 Gln Gln Gly Ile Lys Thr Lys Thr Leu Pro Thr Asn His Ala PheHis 785 790 795 800 Ser Pro His Thr Asn Pro Ile Leu Asn Gln Leu His GlnHis Thr Gln 805 810 815 Thr Leu Thr Tyr His Pro Pro His Thr Pro Leu IleThr Ala Asn Thr 820 825 830 Pro Pro Asp Gln Leu Leu Thr Pro His Tyr TrpThr Gln Gln Ala Arg 835 840 845 Asn Thr Val Asp Tyr Ala Thr Thr Thr GlnThr Leu His Gln His Gly 850 855 860 Val Thr Thr Tyr Ile Glu Leu Gly ProAsp Asn Thr Leu Thr Thr Leu 865 870 875 880 Thr His Asp Asn Leu Pro AsnThr Pro Thr Thr Thr Leu Thr Leu Thr 885 890 895 His Pro His His His ProGln Thr His Leu Leu Thr Asn Leu Ala Lys 900 905 910 Thr Thr Thr Thr TrpHis Pro His His Tyr Thr His His His Asn Gln 915 920 925 Pro His Thr HisThr His Leu Asp Leu Pro Thr Tyr Pro Phe Gln His 930 935 940 His His TyrTrp Leu Gln Pro Pro Gly Lys Pro Ser Asp Pro Ser Pro 945 950 955 960 SerGlu Gly Arg Glu Gln Ala Thr Thr Pro Ser Thr Pro Leu Arg Asp 965 970 975Val Leu Val Gly Lys Ser Pro Gln Glu Arg Asp Glu Glu Leu Leu Arg 980 985990 Leu Val Arg Thr His Ala Ala Ala Val Leu Gly His Ala Thr Pro Glu 9951000 1005 Val Ile Val Pro Asn Lys Ala Phe Lys Glu Leu Gly Phe Asp SerLeu 1010 1015 1020 Ala Ala Ile Gln Leu Arg Asn Arg Leu Leu Ala Asp ValAsp Leu Pro 1025 1030 1035 1040 Leu Pro Ala Thr Leu Ile Phe Asp Tyr ProThr Pro Met Ala Leu Cys 1045 1050 1055 Gln Phe Leu Arg Ala Ala Ile ValGly Ala Asp Thr Gly Thr Thr Thr 1060 1065 1070 Arg Leu Pro Leu Thr AlaVal Pro Ala Asp Glu Pro Ile Ala Ile Val 1075 1080 1085 Gly Met Ala CysArg Tyr Pro Gly Asp Val Arg Thr Val Asp Asp Leu 1090 1095 1100 Trp GlnVal Val Ser Gly Gly His Asp Ala Ile Gly Gly Phe Pro Thr 1105 1110 11151120 Asn Arg Gly Trp Asp Leu Asp Thr Leu Tyr Asn Pro Asp Pro Asp His1125 1130 1135 His Gly Thr Ser Tyr Thr Arg Ser Gly Gly Phe Leu Tyr AspAla Gly 1140 1145 1150 Asn Phe Asp Pro Asp Phe Phe Gly Ile Ser Pro ArgGlu Ala Leu Ala 1155 1160 1165 Met Asp Pro Gln Gln Arg Leu Leu Leu GluThr Ala Trp Glu Ser Ile 1170 1175 1180 Glu His Ala Cys Ile Asn Pro AspSer Leu Arg Gly Thr Pro Thr Gly 1185 1190 1195 1200 Val Phe Ala Gly LeuThr Tyr His Asp Tyr Ala Ala Arg Phe Pro Thr 1205 1210 1215 Ala Pro AlaGly Phe Glu Gly Tyr Leu Gly His Gly Ser Ala Gly Ser 1220 1225 1230 IleAla Ser Gly Arg Val Ala Tyr Ala Leu Gly Leu Glu Gly Pro Ala 1235 12401245 Leu Thr Val Asp Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu1250 1255 1260 Ala Cys Gln Ala Leu Arg Ser Gly Glu Cys Ser Met Ala LeuAla Gly 1265 1270 1275 1280 Gly Val Thr Val Met Ser Thr Pro Ala Gly PheVal Glu Phe Ser Arg 1285 1290 1295 Gln Arg Gly Leu Ala Val Asp Gly ArgCys Lys Ala Phe Ser Ala Ala 1300 1305 1310 Ala Asp Gly Thr Gly Trp GlyGlu Gly Val Gly Met Leu Leu Val Glu 1315 1320 1325 Arg Leu Ser Asp AlaArg Arg Leu Gly His Arg Ile Leu Ala Val Val 1330 1335 1340 Arg Gly SerAla Val Asn Gln Asp Gly Ala Ser Asn Gly Leu Thr Ala 1345 1350 1355 1360Pro Asn Gly Pro Ser Gln Glu Arg Val Ile Arg Leu Ala Leu Ala Asn 13651370 1375 Ala Asp Leu Thr Pro Ala Asp Val Asp Ala Val Glu Ala His GlyThr 1380 1385 1390 Gly Thr Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala LeuLeu Ala Thr 1395 1400 1405 Tyr Gly Gln Asp Arg Pro Gly Asn Glu Pro LeuTrp Leu Gly Ser Met 1410 1415 1420 Lys Ser Asn Ile Gly His Ala Gln AlaAla Ala Gly Val Gly Gly Val 1425 1430 1435 1440 Ile Lys Met Val Met AlaLeu Arg Asn Gly Leu Leu Pro Arg Thr Leu 1445 1450 1455 His Val Asp GluPro Ser Pro His Val Asp Trp Ser Ala Gly Ala Val 1460 1465 1470 Gln LeuLeu Thr Glu Thr Val Pro Trp Pro Gly Gly Glu Gly Arg Leu 1475 1480 1485Arg Arg Ala Gly Val Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His 14901495 1500 Val Ile Leu Glu Glu Ala Pro Ala His Asn Ile Pro Ser Asp ThrPro 1505 1510 1515 1520 Ala Asp Asp Ala Pro Gly Glu Ala Ala Ala Asp AspVal Pro Gly Glu 1525 1530 1535 Ala Ala Gly Asp Asp Ala Gly Thr Gly GlyGlu Ala Thr Gly Pro Ala 1540 1545 1550 Ala Gly Ser Pro Gly Val Trp ProTrp Leu Val Ser Ala Lys Ser Gln 1555 1560 1565 Pro Ala Leu Arg Ala GlnAla Gln Ala Leu His Ala His Leu Thr Asp 1570 1575 1580 His Pro Gly LeuAsp Leu Ala Asp Val Gly Tyr Thr Leu Ala His Ala 1585 1590 1595 1600 ArgAla Val Phe Asp His Arg Ala Thr Leu Ile Ala Ala Asp Arg Asp 1605 16101615 Thr Phe Leu Gln Ala Leu Gln Ala Leu Ala Ala Gly Glu Pro His Pro1620 1625 1630 Ala Val Ile His Ser Ser Ala Pro Gly Gly Thr Gly Thr GlyGlu Ala 1635 1640 1645 Ala Gly Lys Thr Ala Phe Ile Cys Ser Gly Gln GlyThr Gln Arg Pro 1650 1655 1660 Gly Met Ala His Gly Leu Tyr His Thr HisPro Val Phe Ala Ala Ala 1665 1670 1675 1680 Leu Asn Asp Ile Cys Thr HisLeu Asp Pro His Leu Asp His Pro Leu 1685 1690 1695 Leu Pro Leu Leu ThrGln Asp Pro Asn Thr Gln Asp Thr Thr Thr Leu 1700 1705 1710 Glu Glu AlaAla Ala Leu Leu Gln Gln Thr Pro Tyr Ala Gln Pro Ala 1715 1720 1725 LeuPhe Ala Phe Gln Val Ala Leu His Arg Leu Leu Thr Asp Gly Tyr 1730 17351740 His Ile Thr Pro His Tyr Tyr Ala Gly His Ser Leu Gly Glu Ile Thr1745 1750 1755 1760 Ala Ala His Leu Ala Gly Ile Leu Thr Leu Thr Asp AlaThr Thr Leu 1765 1770 1775 Ile Thr Gln Arg Ala Thr Leu Met Gln Thr MetPro Pro Gly Thr Met 1780 1785 1790 Thr Thr Leu His Thr Thr Pro His HisIle Thr His His Leu Thr Ala 1795 1800 1805 His Glu Asn Asp Leu Ala IleAla Ala Ile Asn Thr Pro Thr Ser Leu 1810 1815 1820 Val Ile Ser Gly ThrPro His Thr Val Gln His Ile Thr Thr Leu Cys 1825 1830 1835 1840 Gln GlnGln Gly Ile Lys Thr Lys Thr Leu Pro Thr Lys Asn Ala Phe 1845 1850 1855His Ser Pro His Thr Asn Pro Ile Leu Asn Gln Leu His Gln His Thr 18601865 1870 Gln Thr Leu Thr Tyr His Pro Pro His Thr Pro Leu Ile Thr AlaAsn 1875 1880 1885 Thr Pro Pro Asp Gln Leu Leu Thr Pro His Tyr Trp ThrGln Gln Ala 1890 1895 1900 Arg Asn Thr Val Asp Tyr Ala Thr Thr Thr GlnThr Leu His Gln His 1905 1910 1915 1920 Gly Val Thr Thr Tyr Ile Glu LeuGly Pro Asp Asn Thr Leu Thr Thr 1925 1930 1935 Leu Thr His His Asn LeuPro Asn Thr Pro Thr Thr Thr Leu Thr Leu 1940 1945 1950 Thr His Pro HisHis His Pro Gln Thr His Leu Leu Thr Asn Leu Ala 1955 1960 1965 Lys ThrThr Thr Thr Trp His Pro His His Tyr Thr His His His Asn 1970 1975 1980Gln Pro His Thr His Thr His Leu Asp Leu Pro Thr Tyr Pro Phe Gln 19851990 1995 2000 His Gln His Tyr Trp Leu Glu Ser Thr Gln Pro Gly Ala GlySer Gly 2005 2010 2015 Ser Gly Ser Gly Ser Gly Arg Ala Gly Thr Ala GlyGly Thr Ala Glu 2020 2025 2030 Val Glu Ser Arg Phe Trp Asp Ala Val AlaArg Gln Asp Leu Glu Thr 2035 2040 2045 Val Ala Thr Thr Leu Ala Val ProPro Ser Ala Gly Leu Asp Thr Val 2050 2055 2060 Val Pro Ala Leu Ser AlaTrp His Arg His Gln His Asp Gln Ala Arg 2065 2070 2075 2080 Ile Asn ThrTrp Thr Tyr Gln Glu Thr Trp Lys Pro Leu Thr Leu Pro 2085 2090 2095 ThrThr His Gln Pro His Gln Thr Trp Leu Ile Ala Ile Pro Glu Thr 2100 21052110 Gln Thr His His Pro His Ile Thr Asn Ile Leu Thr Asn Leu His His2115 2120 2125 His Gly Ile Thr Pro Ile Pro Leu Thr Leu Asn His Thr HisThr Asn 2130 2135 2140 Pro Gln His Leu His His Thr Arg Gln Gln Ala GlnAsn His Thr Thr 2145 2150 2155 2160 Gly Pro Ile Thr Gly Leu Leu Ser LeuLeu Ala Leu Asp Glu Thr Pro 2165 2170 2175 His Pro His His Pro His ThrPro Thr Gly Thr Leu Leu Asn Leu Thr 2180 2185 2190 Leu Thr Gln Thr HisThr Gln Thr His Pro Pro Thr Pro Leu Trp Tyr 2195 2200 2205 Ala Thr ThrAsn Ala Thr Thr Thr His Pro Asn Asp Pro Leu Thr His 2210 2215 2220 ProThr Gln Ala Gln Thr Trp Gly Leu Ala Arg Thr Thr Leu Leu Glu 2225 22302235 2240 His Pro Thr His Thr Ala Gly Ile Ile Asp Leu Pro Thr Thr ProThr 2245 2250 2255 Pro His Thr Leu His His Leu Thr Gln Thr Leu Thr GlnPro His His 2260 2265 2270 Gln Thr Gln Leu Ala Ile Arg Thr Thr Gly ThrHis Thr Arg Arg Leu 2275 2280 2285 Thr Pro Thr Thr Leu Thr Pro Thr HisGln Pro Pro Thr Pro Thr Pro 2290 2295 2300 His Gly Thr Thr Leu Ile ThrGly Gly Thr Gly Ala Leu Ala Thr His 2305 2310 2315 2320 Leu Thr His HisLeu Thr Thr His Gln Pro Thr Gln His Leu Leu Leu 2325 2330 2335 Thr SerArg Thr Gly Pro His Thr Pro His Ala Gln His Leu Thr Thr 2340 2345 2350Gln Leu Gln Gln Lys Gly Ile His Leu Thr Ile Thr Thr Cys Asp Thr 23552360 2365 Ser Asn Pro Asp Gln Leu Gln Gln Leu Leu Asn Thr Ile Pro ProGln 2370 2375 2380 His Pro Leu Thr Thr Val Ile His Thr Ala Gly Ile LeuAsp Asp Ala 2385 2390 2395 2400 Thr Leu Thr Asn Leu Thr Pro Thr Gln LeuAsn Asn Val Leu Arg Ala 2405 2410 2415 Lys Ala His Ser Ala His Leu LeuHis Gln Leu Thr Gln His Thr Pro 2420 2425 2430 Leu Asn Ala Phe Val LeuTyr Ser Ser Ala Ala Ala Thr Phe Gly Ala 2435 2440 2445 Pro Gly Gln AlaAsn Tyr Ala Ala Ala Asn Ala Tyr Leu Asp Ala Leu 2450 2455 2460 Ala HisHis Arg His Thr His His Leu Pro Ala Thr Ser Ile Ala Trp 2465 2470 24752480 Gly Thr Trp Gln Gly Asn Gly Leu Ala Thr Gly Gln Val Ser Glu His2485 2490 2495 Leu Arg Arg Arg Gly Met Phe Ala Met Pro Pro Glu Leu AlaVal Thr 2500 2505 2510 Ala Val Asp Gly Ala Ile Ala Ser Gly Arg Pro SerLeu Leu Val Ala 2515 2520 2525 Asp Ile Asp Trp Lys Lys Leu Gly Pro ValLeu Ser Ser Lys Ser Ser 2530 2535 2540 Val Leu Leu Glu Asp Leu Pro GlnAla Gln Gly Thr Glu Glu Ala Arg 2545 2550 2555 2560 Ser Thr Val Glu GlnThr Glu Ser Thr Asn Leu Arg Gln Leu Leu Met 2565 2570 2575 Gly Arg SerArg Ser Glu Gln Glu Glu Glu Leu Leu Ser Leu Val Arg 2580 2585 2590 IleHis Ser Ala Ala Val Leu Gly Arg Asp Asp Ser Glu Ala Ile Pro 2595 26002605 Pro Gly Arg Leu Phe Arg Asp Leu Gly Phe Asp Ser Leu Ala Ala Val2610 2615 2620 Glu Leu Arg Asn His Leu Ala Ala Gln Thr Glu Leu Ala LeuPro Thr 2625 2630 2635 2640 Thr Leu Val Phe Asp Tyr Pro Ser Pro Thr LysLeu Ala Gln Phe Leu 2645 2650 2655 Leu Ser Glu Ile Ala Glu Phe Gln ProAsp Asn Ser Thr Pro Leu Pro 2660 2665 2670 Arg Pro Arg Ala Glu Leu AspGlu Pro Ile Ala Ile Val Gly Met Ala 2675 2680 2685 Cys Arg Phe Pro GlyGly Val Thr Ser Ala Asp Asp Phe Trp Asp Leu 2690 2695 2700 Ile Ser SerGlu Gln Asp Ala Ile Gly Gly Phe Pro Thr Asp Arg Gly 2705 2710 2715 2720Trp Asp Leu Asp Thr Leu Tyr Asp Pro Asp Pro Asp His Pro Gly Thr 27252730 2735 Cys Tyr Thr Arg Asn Gly Gly Phe Leu Tyr Asp Ala Gly His PheAsp 2740 2745 2750 Ala Glu Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu AlaMet Asp Pro 2755 2760 2765 Gln Gln Arg Leu Leu Leu Glu Thr Ala Trp GluThr Ile Glu His Ala 2770 2775 2780 Gly Ile Asn Pro His Thr Leu His GlyThr Pro Thr Gly Val Phe Thr 2785 2790 2795 2800 Gly Thr Asn Gly Gln AspHis Ala Ala His Ile Arg Gln Ala Pro Ser 2805 2810 2815 Gly Thr Glu GlyPhe Val Leu Thr Gly Ala Ala Thr Ser Ile Ala Ser 2820 2825 2830 Gly ArgIle Ser Tyr Ile Leu Gly Leu Glu Gly Pro Ala Val Thr Leu 2835 2840 2845Asp Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln 28502855 2860 Ser Leu Arg Ser Gly Glu Cys Thr Met Ala Leu Ala Gly Gly AlaThr 2865 2870 2875 2880 Val Met Thr Thr Pro Ile Thr Phe Thr Glu Phe AlaArg Gln Arg Gly 2885 2890 2895 Leu Ala Pro Asp Gly Arg Cys Lys Ala PheSer Ala Ala Ala Asp Gly 2900 2905 2910 Thr Gly Trp Gly Glu Gly Val GlyMet Leu Leu Val Glu Arg Leu Ser 2915 2920 2925 Asp Ala Arg Arg Asn GlyHis Arg Val Leu Ala Val Val Arg Gly Ser 2930 2935 2940 Ala Val Asn GlnAsp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn Gly 2945 2950 2955 2960 ProSer Gln Gln Arg Val Ile Arg Gln Ala Leu Ala Asn Ala Asp Leu 2965 29702975 Thr Pro Ala Asp Val Asp Ala Val Glu Ala His Gly Thr Gly Thr Thr2980 2985 2990 Leu Gly Asp Pro Ile Glu Ala Gln Ala Ile Leu Ala Thr TyrGly Gln 2995 3000 3005 Asp Arg Pro Gly Asn Gly Pro Leu Trp Leu Gly SerVal Lys Ser Asn 3010 3015 3020 Val Gly His Thr Gln Ala Ala Ala Gly ValAla Gly Val Ile Lys Met 3025 3030 3035 3040 Val Met Ala Leu Arg His ArgThr Leu Pro Pro Thr Leu His Ala Asp 3045 3050 3055 Glu Pro Ser Pro HisVal Asp Trp Ser Ala Gly Ala Val Gln Leu Leu 3060 3065 3070 Thr Glu ThrVal Pro Trp Pro Gly Gly Glu Gly Arg Pro Arg Arg Ala 3075 3080 3085 GlyVal Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val Ile Leu 3090 30953100 Glu Glu Ala Pro Ala Asp Asp Val Pro Gly Gly Pro Pro Ala Asp Glu3105 3110 3115 3120 Asp Ala Gly Ser Gly Glu Glu Ala Ala Ala Gly Ser ProGly Val Trp 3125 3130 3135 Pro Trp Leu Val Ser Ala Lys Ser Gln Pro AlaLeu Arg Ala Gln Ala 3140 3145 3150 Gln Ala Leu His Ala His Leu Thr AspHis Pro Gly Leu Asp Leu Ala 3155 3160 3165 Asp Val Gly Tyr Thr Leu AlaHis Ala Arg Ala Val Phe Asp His Arg 3170 3175 3180 Ala Thr Leu Ile AlaAla Asp Arg Asp Thr Phe Leu Gln Ala Leu Gln 3185 3190 3195 3200 Ala LeuAla Ala Gly Glu Pro His Pro Ala Val Ile His Ser Ser Ala 3205 3210 3215Pro Gly Gly Thr Gly Thr Gly Glu Ala Ala Gly Lys Thr Ala Phe Ile 32203225 3230 Cys Ser Gly Gln Gly Thr Gln Arg Pro Gly Met Ala His Gly LeuTyr 3235 3240 3245 His Thr His Pro Val Phe Ala Ala Ala Leu Asn Asp IleCys Thr His 3250 3255 3260 Leu Asp Pro His Leu Asp His Pro Leu Leu ProLeu Leu Thr Gln Asn 3265 3270 3275 3280 Asp Asn Asp Asn Asp Asn Glu AspAla Ala Ala Leu Leu Gln Gln Thr 3285 3290 3295 Pro Tyr Ala Gln Pro AlaLeu Phe Ala Phe Gln Val Ala Leu His Arg 3300 3305 3310 Leu Leu Thr AspGly Tyr His Ile Thr Pro His Tyr Tyr Ala Gly His 3315 3320 3325 Ser LeuGly Glu Ile Thr Ala Ala His Leu Ala Gly Ile Leu Thr Leu 3330 3335 3340Thr Asp Ala Thr Thr Leu Ile Thr Gln Arg Ala Thr Leu Met Gln Thr 33453350 3355 3360 Met Pro Pro Gly Thr Met Thr Thr Leu His Thr Thr Pro HisHis Ile 3365 3370 3375 Thr His His Leu Thr Ala His Glu Asn Asp Leu AlaIle Ala Ala Ile 3380 3385 3390 Asn Thr Pro Thr Ser Leu Val Ile Ser GlyThr Pro His Thr Val Gln 3395 3400 3405 His Ile Thr Thr Leu Cys Gln GlnGln Gly Ile Lys Thr Lys Thr Leu 3410 3415 3420 Pro Thr Asn His Ala PheHis Ser Pro His Thr Asn Pro Ile Leu Asn 3425 3430 3435 3440 Gln Leu HisGln His Thr Gln Thr Leu Thr Tyr His Pro Pro His Thr 3445 3450 3455 ProLeu Ile Thr Ala Asn Thr Pro Pro Asp Gln Leu Leu Thr Pro His 3460 34653470 Tyr Trp Thr Gln Gln Ala Arg Asn Thr Val Asp Tyr Ala Thr Thr Thr3475 3480 3485 Gln Thr Leu His Gln His Gly Val Thr Thr Tyr Ile Glu LeuGly Pro 3490 3495 3500 Asp Asn Thr Leu Thr Thr Leu Thr His His Asn LeuPro Asn Thr Pro 3505 3510 3515 3520 Thr Thr Thr Leu Thr Leu Thr His ProHis His His Pro Gln Thr His 3525 3530 3535 Leu Leu Thr Asn Leu Ala LysThr Thr Thr Thr Trp His Pro His His 3540 3545 3550 Tyr Thr His His HisAsn Gln Pro His Thr His Thr His Leu Asp Leu 3555 3560 3565 Pro Thr TyrPro Phe Gln His His His Tyr Trp Leu Glu Leu Pro Ser 3570 3575 3580 AlaGln Thr Ser Pro Gly Gln Arg Arg Ser Arg Arg Ser Ala Pro Asp 3585 35903595 3600 Thr Ala Glu Ser Glu Phe Trp Asp Ala Val Asn Glu Glu Asp LeuGln 3605 3610 3615 Ser Leu Ala Glu Thr Leu Asp Ile Asp Ala Ser Ala LeuAsp Thr Val 3620 3625 3630 Val Pro Ala Leu Ser Ala Trp His Arg His GlnHis Asp Gln Ala Arg 3635 3640 3645 Ile Asn Thr Trp Thr Tyr Gln Glu ThrTrp Lys Pro Leu Thr Leu Pro 3650 3655 3660 Thr Thr His Gln Pro His GlnThr Trp Leu Ile Ala Ile Pro Glu Thr 3665 3670 3675 3680 Gln Thr His HisPro His Ile Thr Asn Ile Leu Thr Asn Leu His His 3685 3690 3695 His GlyIle Thr Pro Ile Pro Leu Thr Val Asn His Thr His Thr Asn 3700 3705 3710Pro Gln His Leu His His Thr Leu His His Thr Arg Gln Gln Ala Gln 37153720 3725 Asn His Thr Thr Gly Pro Ile Thr Gly Leu Leu Ser Leu Leu AlaLeu 3730 3735 3740 Asp Glu Thr Pro His Pro His His Pro His Thr Pro ThrGly Thr Leu 3745 3750 3755 3760 Leu Asn Leu Thr Leu Pro Gln Thr His ThrGln Thr His Pro Pro Thr 3765 3770 3775 Pro Leu Trp Tyr Ala Thr Thr AsnAla Thr Thr Thr His Pro Asn Asp 3780 3785 3790 Pro Leu Thr His Pro ThrGln Ala Gln Thr Trp Gly Leu Ala Arg Thr 3795 3800 3805 Thr Leu Leu GluHis Pro Thr His Thr Ala Gly Ile Ile Asp Leu Pro 3810 3815 3820 Thr ThrPro Thr Pro His Thr Leu His His Leu Thr Gln Thr Leu Thr 3825 3830 38353840 Gln Pro His His Gln Thr Gln Leu Ala Ile Arg Thr Thr Gly Thr His3845 3850 3855 Thr Arg Arg Leu Thr Pro Thr Thr Leu Thr Pro Thr His GlnPro Pro 3860 3865 3870 Thr Pro Thr Pro His Gly Thr Thr Leu Ile Thr GlyGly Thr Gly Ala 3875 3880 3885 Leu Ala Thr His Leu Thr His His Leu ThrThr His Gln Pro Thr Gln 3890 3895 3900 His Leu Leu Leu Thr Ser Arg ThrGly Pro His Thr Pro His Ala Gln 3905 3910 3915 3920 His Leu Thr Thr GlnLeu Gln Gln Lys Gly Ile His Leu Thr Ile Thr 3925 3930 3935 Thr Cys AspThr Ser Asn Pro Asp Gln Leu Gln Gln Leu Leu Asn Thr 3940 3945 3950 IlePro Pro Gln His Pro Leu Thr Thr Val Ile His Thr Ala Gly Val 3955 39603965 Asn Leu Phe Ala Pro Val Ser Glu Thr Asp Ala Glu Ser Phe Ser Ser3970 3975 3980 Val Thr Ala Ala Lys Ala Thr Gly Ala Ala Ile Leu His GluLeu Leu 3985 3990 3995 4000 Leu Asp His Glu Thr Leu Glu His Phe Ile LeuPhe Ser Ser Gly Ala 4005 4010 4015 Gly Ala Trp Gly Ser Gly Asn Gln CysAla Tyr Ser Ala Ala Asn Ala 4020 4025 4030 Tyr Leu Asp Ala Leu Ala ThrHis Arg Gln Thr His Gly Leu Pro Gly 4035 4040 4045 Ala Ser Ile Ala TrpGly Pro Trp Ala Gly Lys Gly Met Ser Ala Gly 4050 4055 4060 Asp Ala AlaHis Gly Tyr Leu Glu Lys Arg Gly Ile Leu Pro Met Glu 4065 4070 4075 4080Pro Arg Met Ala Leu Ala Ala Phe His Arg Ala Arg Ala Gln Arg Pro 40854090 4095 Asn Ser Asn Leu Ile Ile Ala Asp Ile Asp Trp Glu Arg Phe ValPro 4100 4105 4110 Ala Phe Thr Ala Arg Arg His Ser Pro Leu Ile Glu AspIle Pro Glu 4115 4120 4125 Val Arg Gln Ala Ala Gln Glu Leu Glu Ala AlaAla Ser Thr Ala Lys 4130 4135 4140 Thr Thr Thr Ala Gln Pro Ile Ala ThrSer Leu Arg Glu Arg Leu Ala 4145 4150 4155 4160 Arg Leu Thr Ser Ser LysGln Asn Gln Val Leu Leu Gly Leu Ile Arg 4165 4170 4175 Thr Gly Ile CysThr Val Leu Gly Leu Arg Asn Pro Glu Gly Ile Glu 4180 4185 4190 Asp GlnArg Ala Phe Arg Asp Leu Gly Phe Asp Ser Leu Thr Ser Ala 4195 4200 4205Gln Phe Ser Lys Glu Leu Ala Lys Glu Thr Gly Leu Pro Leu Pro Pro 42104215 4220 Ser Leu Val Phe Asp Tyr Pro Thr Pro Gln Glu Cys Ala Ala HisLeu 4225 4230 4235 4240 Arg Thr Gln Leu Val Asp Leu Asp Asp Glu Glu AspAla Ala Leu Ser 4245 4250 4255 Asn Ala Leu Pro Gln Val Ala His Arg ArgThr Val Glu Asp Glu Pro 4260 4265 4270 Ile Ala Ile Ile Gly Met Ala CysArg Phe Pro Gly Gly Val Arg Ser 4275 4280 4285 Ala Asp Asp Leu Trp GluLeu Leu Ala Ser Gly Lys Asp Ala Ile Gly 4290 4295 4300 Val Phe Pro ThrAsp Arg Gly Trp Asp Leu Asp Thr Leu Tyr Asp Pro 4305 4310 4315 4320 AspPro Asp His Pro Gly Thr Cys Tyr Thr Arg Asn Gly Gly Phe Leu 4325 43304335 Tyr Gly Ala Gly His Phe Asp Ala Glu Phe Phe Gly Ile Ser Pro Arg4340 4345 4350 Glu Ala Leu Ala Met Asp Pro Gln Gln Arg Leu Leu Leu GluThr Ala 4355 4360 4365 Trp Glu Thr Ile Glu His Ala Gly Ile Asn Pro HisThr Leu His Gly 4370 4375 4380 Thr Pro Thr Gly Val Phe Ala Gly Ile AsnAla Gln Asp His Ala Ala 4385 4390 4395 4400 His Ile Arg Gln Ser Arg AspVal Glu Thr Ile Glu Gly Tyr Ala Leu 4405 4410 4415 Thr Gly Ser Ser GlySer Val Ala Ser Gly Arg Val Ala Tyr Thr Leu 4420 4425 4430 Gly Leu GluGly Pro Ala Val Ser Val Asp Thr Ala Cys Ser Ser Ser 4435 4440 4445 LeuVal Ala Leu His Trp Ala Ala Gln Ala Leu Arg Ala Gly Glu Cys 4450 44554460 Ser Met Ala Leu Ala Gly Gly Val Thr Val Met Ser Ser Pro Gly Thr4465 4470 4475 4480 Phe Val Glu Phe Ser Arg Gln Arg Gly Leu Ala Ala AspGly Arg Cys 4485 4490 4495 Lys Ala Tyr Ser Ala Ala Ala Asp Gly Thr GlyTrp Ala Glu Gly Val 4500 4505 4510 Gly Met Leu Leu Val Glu Arg Leu SerAsp Ala Arg Arg Asn Gly His 4515 4520 4525 Arg Val Leu Ala Val Val ArgGly Ser Ala Val Asn Gln Asp Gly Ala 4530 4535 4540 Ser Asn Gly Leu ThrAla Pro Asn Gly Pro Ser Gln Gln Arg Val Ile 4545 4550 4555 4560 Arg GlnAla Leu Ala Asn Ala Gly Leu Thr Pro Ala Asp Val Asp Ala 4565 4570 4575Val Glu Gly His Gly Thr Gly Thr Thr Leu Gly Asp Pro Ile Glu Ala 45804585 4590 Gln Ala Leu Leu Ala Ala Tyr Gly Gln His Arg Pro His His ArgPro 4595 4600 4605 Leu Trp Leu Gly Ser Leu Lys Ser Asn Ile Gly His AlaGln Ala Ala 4610 4615 4620 Ala Gly Val Gly Gly Val Ile Lys Met Val MetAla Leu Arg Asn Gly 4625 4630 4635 4640 Leu Leu Pro Gln Thr Leu His ValAsp Glu Pro Thr Pro Gln Val Asp 4645 4650 4655 Trp Ser Thr Gly Ala ValGln Leu Leu Thr Gln Pro Val Pro Trp Pro 4660 4665 4670 Ala Asp Pro AlaGly Arg Pro Arg His Ala Gly Val Ser Ser Phe Gly 4675 4680 4685 Val SerGly Thr Asn Ala His Ile Ile Leu Glu Glu Ala Pro Thr Pro 4690 4695 4700Gln Asp Ser Asp Thr Asp Asp Glu Pro Pro Ala Asn Ala Pro Ala Leu 47054710 4715 4720 Pro His Pro Leu Pro Leu Pro Val Pro Val Ser Ala Arg SerGlu Ala 4725 4730 4735 Gly Leu Arg Ala Gln Ala Gln Ala Leu Arg Gln TyrVal Ala Ala Arg 4740 4745 4750 Pro Asp Met Ser Pro Ala Asp Ile Gly AlaGly Leu Ala Arg Gly Arg 4755 4760 4765 Ala Val Leu Glu His Arg Ala ValIle Leu Ala Ala Asp Arg Glu Glu 4770 4775 4780 Leu Ala Gln Ala Leu ThrAla Leu Ala Ala Gly Glu Pro His Pro His 4785 4790 4795 4800 Ile Thr ThrGly His Thr Arg Gly Gly Asp Arg Gly Gly Val Val Phe 4805 4810 4815 ValPhe Pro Gly Gln Gly Gly Gln Trp Ala Gly Met Gly Leu Thr Leu 4820 48254830 Leu Thr Ser Ser Pro Val Phe Ala Glu His Ile Asp Ala Cys Glu Lys4835 4840 4845 Ala Leu Thr Pro Trp Val Pro Trp Ser Leu Thr Asp Ile LeuHis Arg 4850 4855 4860 Asp Pro Asp Asp Pro Ala Trp Gln Gln Ala Asp ValVal Gln Pro Val 4865 4870 4875 4880 Leu Phe Ser Ile Met Val Ser Leu AlaAla Leu Trp Arg Ser Tyr Gly 4885 4890 4895 Ile Glu Pro Asp Ala Val LeuGly His Ser Gln Gly Glu Ile Ala Ala 4900 4905 4910 Ala His Ile Cys GlyAla Leu Ser Leu Lys Asp Ala Ala Lys Thr Val 4915 4920 4925 Ala Leu ArgSer Arg Ala Leu Ala Ala Val Arg Gly Arg Gly Ala Met 4930 4935 4940 AlaSer Leu Pro Leu Pro Ala Gln Asp Val Gln Gln Leu Ile Ser Glu 4945 49504955 4960 Arg Trp Glu Gly Gln Leu Trp Val Ala Ala Leu Asn Gly Pro HisSer 4965 4970 4975 Thr Thr Val Ser Gly Asp Thr Lys Ala Val Asp Glu ValLeu Ala His 4980 4985 4990 Cys Thr Asp Thr Gly Leu Arg Ala Lys Arg IlePro Val Asp Tyr Ala 4995 5000 5005 Ser His Cys Pro His Val Gln Pro LeuHis Asp Glu Leu Leu His Leu 5010 5015 5020 Leu Gly Asp Ile Thr Pro GlnPro Ser Thr Val Pro Phe Phe Ser Thr 5025 5030 5035 5040 Val Glu Gly ThrTrp Leu Asp Thr Thr Thr Leu Asp Ala Ala Tyr Trp 5045 5050 5055 Tyr ArgAsn Leu His Gln Pro Val Arg Phe Ser His Ala Ile Gln Thr 5060 5065 5070Leu Thr Asp Asp Gly His Arg Ala Phe Ile Glu Ile Ser Pro His Pro 50755080 5085 Thr Leu Val Pro Ala Ile Glu Asp Thr Thr Glu Asn Thr Thr GluAsn 5090 5095 5100 Ile Thr Ala Thr Gly Ser Leu Arg Arg Gly Asp Asn AspThr His Arg 5105 5110 5115 5120 Phe Leu Thr Ala Leu Ala His Thr His ThrThr Gly Ile Gly Thr Pro 5125 5130 5135 Thr Thr Trp His His His Tyr ThrGln Thr His Pro His Pro Asn Pro 5140 5145 5150 His Thr His Leu Asp LeuPro Thr Tyr Pro Phe Gln His Gln His Tyr 5155 5160 5165 Trp Leu Gln ProPro Thr Thr Thr Thr Asp Leu Thr Thr Thr Gly Leu 5170 5175 5180 Thr ProThr His His Pro Leu Leu Thr Ala Thr Leu Thr Leu Ala Asp 5185 5190 51955200 Asn Asn Thr Gln Leu Leu Thr Gly Arg Leu Ser Leu Arg Thr His Pro5205 5210 5215 Trp Leu Thr Asp His Thr Val Ala Gly Met Val Leu Leu ProGly Thr 5220 5225 5230 Ala Leu Leu Glu Leu Ala Leu Gln Ala Gly Glu ArgVal Asp Cys Pro 5235 5240 5245 Arg Val Glu Glu Leu Thr Leu His Ala ProLeu Val Ile Pro His Thr 5250 5255 5260 Glu Asp Val Thr Leu Gln Val ThrVal Arg Ala Ala Asp Glu Ser Gly 5265 5270 5275 5280 His Arg Ala Leu AlaIle His Ser Tyr Ser Gly Thr Ala Ser Ser Ala 5285 5290 5295 Asp Arg GluTrp Thr Arg His Ala Thr Gly Leu Leu Thr His His Ala 5300 5305 5310 AspThr Asp His Arg Ala Asp Thr His Thr Asp Ala Cys Leu Gly Gly 5315 53205325 Ser Trp Pro Pro Pro Gly Ala Gln Pro Ile Glu Leu Gly Asp Val Tyr5330 5335 5340 Gly Arg Met Ala Ala Asp Ser Asp Ile Ala Tyr Gly Pro ValPhe Gln 5345 5350 5355 5360 Gly Leu His Ala Ala Trp Arg Phe Gly Asp AspVal Leu Ala Glu Val 5365 5370 5375 Arg Leu Pro Glu Glu Ala Leu Arg AspAla Pro Ala Ala Ala Phe Gly 5380 5385 5390 Val His Pro Ala Leu Leu AspAla Ala Leu His Ala Thr Ala Leu Thr 5395 5400 5405 Pro Gln Asn Gly AspGly Ser Thr Glu Asn Val Ala Gln Glu Ser Met 5410 5415 5420 Pro Asp ArgAla Ala His Gln Ala Arg Leu Pro Phe Ser Trp Ser Gly 5425 5430 5435 5440Val Ser Leu His Thr Ala Gly Ser Ser Val Leu Arg Val Arg Leu Ser 54455450 5455 Arg Ser Pro Gln His Gly Asn Ala Val Ala Leu Thr Ala Ala AspGlu 5460 5465 5470 Asp Gly Arg Pro Val Val Thr Ile Glu Ser Leu Ala LeuArg Pro Val 5475 5480 5485 Ser Thr Glu Glu Leu Arg Ala Ala Ala Asp ArgThr Pro Glu His Glu 5490 5495 5500 Ser Leu Phe Arg Leu Asp Trp Val SerVal Pro Val Pro Ala Asn Ala 5505 5510 5515 5520 Pro Ser Pro Thr Ala AspArg Pro Trp Ala Val Ile Gly Ala Gly Leu 5525 5530 5535 Pro His Leu ProGly Leu Thr Glu His Glu His Val Thr Ala Tyr Asp 5540 5545 5550 Glu ProAla Asp Leu Leu Leu Ala Leu Asp Arg Gly Ala Pro Pro Pro 5555 5560 5565Gly Val Leu Val Val Gly Gly Val Ala His Thr Glu Ala Arg Glu Tyr 55705575 5580 Ser Ala Glu Ala Pro Gly Glu Arg Gly Thr Glu Ala Cys Glu AlaArg 5585 5590 5595 5600 Pro Asp Val Val His Val Gly Val Val His Thr AlaAla Val His Ala 5605 5610 5615 Ala Ala Ala Gln Met Leu Ala Arg Leu GlnAla Trp Leu Gly Asp Glu 5620 5625 5630 Arg Leu Ala Asp Ser Arg Leu LeuVal Leu Thr Cys Gly Ala Val Ala 5635 5640 5645 Arg Ala Ser Gly Asp AspAla Thr Asp Leu Pro Gly Ala Ala Val Trp 5650 5655 5660 Gly Leu Val ArgSer Ala Gln Ser Glu His Pro Asp Arg Ile Thr Leu 5665 5670 5675 5680 LeuAsp Phe Glu Arg Gly Thr Glu Ala Glu Pro Gly Gln Leu Ala Thr 5685 56905695 Ala Leu Asn Cys Gly Glu Arg Gln Leu Ala Val Arg Pro Gly Gly Leu5700 5705 5710 Phe Thr Pro Arg Leu Val Arg Ala Pro Arg Val Ala Asp AlaVal Pro 5715 5720 5725 Ala Val Pro Ala Val Ala Val Pro Ser Ala Gly HisAla Ala Val Pro 5730 5735 5740 Ala Ala Gly Pro Phe Leu Pro Gly Gly ThrVal Leu Ile Thr Gly Gly 5745 5750 5755 5760 Thr Gly Val Leu Gly Arg LeuVal Ala Arg His Leu Val Glu Ala His 5765 5770 5775 Gly Val Arg His LeuLeu Leu Ala Gly Arg Arg Gly Pro Asp Ala Glu 5780 5785 5790 Gly Ala ProGlu Leu Arg Ala Glu Leu Gly Gly Leu Gly Ala Thr Val 5795 5800 5805 GluVal Val Ala Cys Asp Ala Ala Asp Arg Gln Gln Leu Ala Asp Leu 5810 58155820 Leu Thr Arg Ile Pro Asp Asp Arg Pro Leu Thr Gly Val Val His Ser5825 5830 5835 5840 Ala Gly Ile Leu Asp Asp Gly Val Ile Thr Ser Leu SerPro Glu Arg 5845 5850 5855 Leu Gly Ala Val Leu Arg Ala Lys Ala Asp AlaAla Leu Leu Leu Asp 5860 5865 5870 Glu Leu Thr Arg Gly Ala Glu Leu SerAla Phe Val Met Phe Ser Ser 5875 5880 5885 Ala Ser Ala Val Val Gly SerPro Gly Gln Gly Asn Tyr Ala Ala Ala 5890 5895 5900 Asn Ala Val Leu AspPhe Leu Ala His Arg Arg Arg Ala Glu Gly Leu 5905 5910 5915 5920 Pro AlaVal Ser Leu Ala Trp Gly Leu Trp Glu Glu Gly Thr Gly Met 5925 5930 5935Thr Gly His Leu Asp Val Asp Asp His Ala Arg Ile Ser Arg Ala Gly 59405945 5950 Met Arg Pro Leu Pro Thr Ala Glu Ala Leu Ala Leu Phe Asp AlaAla 5955 5960 5965 Leu Ala Asp Gly Glu Pro Phe Leu Met Pro Ala Arg LeuAsp Leu Thr 5970 5975 5980 Ala Val Arg Ser Gly Ala Ala Ser Ala Pro ValPro Pro Leu Leu Gln 5985 5990 5995 6000 Gly Leu Leu Gln Leu Pro Arg SerArg Ser Ala Ala Ala Ala Pro Gly 6005 6010 6015 His Gly Ala Pro Ala AlaAsp Glu Ala Ala Ala Trp Arg Glu Arg Leu 6020 6025 6030 Ala Arg Gln SerAla Gly Glu Arg Arg Gln Ala Leu Leu Arg Leu Val 6035 6040 6045 Arg SerHis Val Ala Ala Val Leu Gly His Ser Gly Ala Asp Gly Ile 6050 6055 6060Asp Ala Ser Arg Ala Phe Arg Glu Leu Gly Phe Asp Ser Leu Thr Ala 60656070 6075 6080 Val Glu Leu Arg Asn Arg Leu Thr Ala Ala Thr Gly Leu ArgLeu Arg 6085 6090 6095 Ala Thr Leu Ala Phe Asp Phe Pro Thr Pro Ala AlaLeu Ala Glu His 6100 6105 6110 Leu Gly Glu Arg Leu Leu Pro Asp Gln GluAla Thr Gly Glu Gln Ala 6115 6120 6125 Gly Asp Gln Leu Ser Gly Gly SerGlu Glu Asp Val Arg Ser Leu Leu 6130 6135 6140 Thr Ser Ile Pro Ile GlyArg Leu Arg Asp Ala Gly Leu Leu Gly Pro 6145 6150 6155 6160 Leu Leu ThrLeu Ala Asp Thr Gly Arg Gly Ala Ser Gly Ala Ala Ala 6165 6170 6175 GlyPro Glu Asp Ala Pro Pro Ser Gly Gln Asp Thr Pro Ala Pro Val 6180 61856190 Ser Ile Asp Glu Met Asp Ile Asp Asp Leu Met Asp Leu Ala His Gly6195 6200 6205 His Gly Thr Ala Pro Ala Arg Glu Pro Ala Asp Ala Glu AspSer Ser 6210 6215 6220 Ser Ser Arg Asn Arg Thr His His Thr His Glu GlyGlu Thr Ala 6225 6230 6235 6 4881 PRT Streptomyces avermitilis 6 Met AlaAsn Glu Glu Lys Leu Arg Asp Tyr Leu Lys Arg Val Thr Ala 1 5 10 15 AspLeu Leu Asn Val Arg Arg Arg Leu Gln Gln Ile Glu Ser Gly Glu 20 25 30 GlnGlu Pro Ile Ala Ile Val Gly Met Ala Cys Arg Phe Pro Gly Gly 35 40 45 ValGlu Ser Ala Glu Asp Phe Trp Glu Leu Ile Ala Ser Gly Arg Asp 50 55 60 AlaVal Gly Glu Phe Pro Val Asp Arg Gly Trp Asp Val Glu Ala Phe 65 70 75 80Tyr Asp Pro Glu Pro Gly Arg Ala Gly Ser Ser Tyr Thr Arg Arg Gly 85 90 95Gly Phe Leu Glu Gly Ala Ala Glu Phe Asp Ala Gly Phe Phe Gly Ile 100 105110 Ser Pro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln Arg Leu Met Leu 115120 125 Glu Val Ser Trp Glu Ala Leu Glu Arg Ala Gly Ile Asp Pro Ala Thr130 135 140 Leu Arg Gly Ser Arg Thr Gly Val Phe Ala Gly Leu Met Ser GlnAsp 145 150 155 160 Tyr Ala Thr Arg Leu Leu Ser Val Pro Asp Asp Leu AlaGly Tyr Leu 165 170 175 Gly Asn Gly Asn Ala Gly Ser Ile Leu Ser Gly ArgVal Ala Tyr Thr 180 185 190 Phe Gly Phe Glu Gly Pro Ala Val Thr Val AspThr Ala Cys Ser Ser 195 200 205 Ser Leu Val Ala Leu His Leu Ala Cys GlnSer Leu Arg Thr Gly Glu 210 215 220 Ser Ser Phe Ala Leu Ala Gly Gly ValThr Val Met Ser Thr Pro Gly 225 230 235 240 Met Phe Val Glu Phe Ser ArgGln Arg Gly Leu Ser Pro Asp Gly Arg 245 250 255 Cys Lys Ala Tyr Ala SerAla Ala Asp Gly Thr Gly Met Ser Glu Gly 260 265 270 Val Gly Ile Leu LeuLeu Glu Arg Leu Ser Glu Ala Glu Arg Arg Gly 275 280 285 His Arg Val LeuAla Val Val Arg Gly Ser Ala Val Asn Gln Asp Gly 290 295 300 Ala Ser AsnGly Leu Thr Ala Pro Asn Gly Pro Ser Gln Gln Arg Val 305 310 315 320 IleArg Gln Ala Leu Ala Cys Ala Gly Leu Ser Val Ala Asp Val Asp 325 330 335Val Val Glu Gly His Gly Thr Gly Thr Thr Leu Gly Asp Pro Ile Glu 340 345350 Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Arg Ala Gly Asp Thr Pro 355360 365 Val Trp Leu Gly Ser Val Lys Ser Asn Ile Gly His Ala Gln Ala Ala370 375 380 Ala Gly Val Ala Gly Val Ile Lys Met Val Met Ala Leu Arg AlaGly 385 390 395 400 Val Leu Pro Arg Thr Leu His Val Asp Glu Pro Ser SerGln Val Asp 405 410 415 Trp Ser Ser Gly Ser Val Arg Val Leu Ala Asp GluVal Glu Trp Pro 420 425 430 Gly Val Glu Gly Arg Leu Arg Arg Ala Gly ValSer Ala Phe Gly Val 435 440 445 Ser Gly Thr Asn Ala His Val Ile Leu GluGlu Ala Ser Gly Gly Ala 450 455 460 Gly Gly Gly Ala Gly Arg Leu Gln GluLeu Gly Pro Gly Val Val Ser 465 470 475 480 Gly Ser Gly Val Val Pro TrpVal Val Ser Ala Arg Ser Glu Leu Ala 485 490 495 Leu Arg Gly Gln Ala ArgArg Leu Arg Gly Val Val Ala Val Gly Gly 500 505 510 Gly Ala Asp Gly ValGly Val Ser Pro Ala Gly Val Gly Arg Ala Leu 515 520 525 Val Ser Glu ArgSer Val Phe Glu His Arg Ala Val Val Val Ala Glu 530 535 540 Asp Arg AspGlu Phe Leu His Ala Leu Asp Ala Leu Ala Gly Gly Arg 545 550 555 560 ProVal Pro Gly Val Val Glu Gly Arg Thr Thr Ser Gly Glu Leu Ala 565 570 575Val Leu Phe Ala Gly Gln Gly Thr Gln Arg Ala Gly Met Gly Arg Glu 580 585590 Leu Tyr Glu Ala Tyr Pro Val Phe Ala Gln Ala Ile Asp Glu Ile Cys 595600 605 Ala Glu Ala Asp Thr Ala Arg Thr Asp Pro Gly Ala Pro Gly Leu Arg610 615 620 Asp Val Leu Phe Ala Pro Gln Asp Ser Pro Glu Gly Arg Leu IleGlu 625 630 635 640 Asp Thr Gly Phe Ala Gln Pro Ala Leu Phe Ala Phe GluVal Ala Leu 645 650 655 Phe Arg Leu Leu Glu Thr Trp Gly Leu Thr Pro AspTyr Val Leu Gly 660 665 670 His Ser Val Gly Glu Leu Ala Ala Ala His ValAla Gly Met Leu Cys 675 680 685 Leu Ala Asp Ala Val Ala Leu Val Val AlaArg Gly Arg Leu Met Gln 690 695 700 Gly Leu Pro Ser Gly Gly Ala Met ValAla Ile Glu Ala Ser Glu Asp 705 710 715 720 Glu Ile Leu Pro Leu Pro AspGlu Tyr Ala Ser Arg Val Ala His Ala 725 730 735 Ala Val Asn Gly Pro ArgSer Ile Val Leu Ser Gly Asp Glu Asp Ala 740 745 750 Val Leu Asp Leu AlaGln Gln Trp Ala Ala Arg Gly Arg Arg Thr Arg 755 760 765 Arg Leu Arg ThrSer His Ala Phe His Ser Pro His Met Asp Ala Met 770 775 780 Leu Gly AspPhe Arg Arg Ala Ala Glu Gln Val Thr Phe Ser Ala Pro 785 790 795 800 ArgIle Pro Val Val Ser Asn Val Thr Gly Ala Pro Leu Pro Ala Glu 805 810 815Thr Met Cys Thr Pro Asp Tyr Trp Val Glu His Ala Arg Ser Thr Val 820 825830 Arg Phe Ala Asp Gly Ile Ser Trp Leu Gln Glu Gln Gly Val Thr Thr 835840 845 Cys Leu Glu Ile Gly Pro Asp Gly Thr Leu Ser Ala Leu Ala Gln Asp850 855 860 Ser Leu Ser Ala Pro Ala Arg Ala Ile Pro Ala Leu Arg Pro AspGln 865 870 875 880 Pro Glu Ala Arg Ser Val Met Thr Ala Leu Ala Glu LeuPhe Val Ala 885 890 895 Gly Thr Ala Val Glu Trp Ala Gly Val Phe Glu GlyThr Ala Arg Glu 900 905 910 Val Gly Asp Gly Cys Gly Val Glu Leu Pro ThrTyr Ala Phe Glu Arg 915 920 925 Glu Arg Phe Trp Leu Asp Val Glu Glu GlySer Ala Gly Gly Ser Gly 930 935 940 Val Ser Gly Met Trp Gly Gly Pro LeuTrp Glu Ala Val Glu Cys Gly 945 950 955 960 Asp Ala Gly Val Val Ala SerLeu Leu Gly Val Asp Glu Gly Ala Ser 965 970 975 Leu Gly Ala Val Val SerAla Leu Gly Glu Trp Gly Arg Val Arg His 980 985 990 Glu Arg Glu Val ValAsp Gly Trp Arg Tyr Arg Glu Val Trp Arg Pro 995 1000 1005 Val Ser GlyGly Gly Val Gly Gly Leu Ser Gly Ala Trp Leu Val Val 1010 1015 1020 SerGlu Gly Glu Ala Gly Pro Val Asp Val Val Ala Glu Gly Leu Glu 1025 10301035 1040 Arg Cys Gly Ala Arg Val Val Arg Val Glu Val Glu Ala Gly CysVal 1045 1050 1055 Ser Arg Glu Val Leu Ala Gly His Leu Arg Glu Ala ValAsp Gly Glu 1060 1065 1070 Ala Val Gly Gly Val Val Ser Leu Val Gly TrpGly Ser Gly Val Val 1075 1080 1085 Gln Ala Gly Val Ala Ser Val Gly LeuVal Gln Ala Leu Gly Asp Val 1090 1095 1100 Gly Val Gly Ala Arg Leu TrpCys Val Thr Gly Gly Ala Val Ser Val 1105 1110 1115 1120 Gly Gly Arg AspAla Val Trp Gly Pro Ala Ser Gly Val Val Trp Gly 1125 1130 1135 Leu GlyArg Val Val Gly Ala Glu Ala Pro Asp Arg Trp Gly Gly Leu 1140 1145 1150Val Asp Val Pro Glu Leu Val Asp Glu Arg Val Val Asp Gly Leu Val 11551160 1165 Gly Val Leu Ala Gly Val Gly Gly Gly Gly Glu Ser Glu Phe AlaVal 1170 1175 1180 Arg Ser Ser Gly Ala Phe Val Arg Arg Leu Val Arg AlaPro Leu Glu 1185 1190 1195 1200 Glu Ala Val Ala Glu Arg Glu Trp Arg ProArg Gly Thr Val Leu Val 1205 1210 1215 Thr Gly Gly Thr Gly Glu Leu GlyAla His Val Ala Arg Trp Met Ala 1220 1225 1230 Arg Arg Gly Ala Glu HisLeu Leu Leu Val Ser Arg Arg Gly Glu Ser 1235 1240 1245 Ala Gln Gly ValGlu Glu Leu Arg Ala Asp Leu Met Gly Leu Gly Ala 1250 1255 1260 Arg ValSer Val Val Ala Cys Asp Ala Ala Asp Arg Glu Ala Leu Ala 1265 1270 12751280 Glu Val Leu Arg Ser Ala Val Pro Ala Glu Cys Pro Leu Gly Val Val1285 1290 1295 Val His Ala Ala Gly Val Val Asp Asp Gly Val Leu Glu GlyLeu Ser 1300 1305 1310 Ser Glu Arg Val Thr Gly Val Leu Arg Ala Lys AlaLeu Ala Ala Trp 1315 1320 1325 Asn Leu His Glu Leu Thr Arg Gly Ala AspLeu Ser Gly Phe Val Val 1330 1335 1340 Phe Ser Ser Ala Ala Ala Thr PheGly Pro Ala Gly Gln Gly Ser Tyr 1345 1350 1355 1360 Ala Ala Ala Asn AlaTyr Val Glu Ala Ile Val Arg His Arg Arg Gly 1365 1370 1375 Glu Gly LeuPro Gly Leu Ala Val Ala Trp Gly Pro Trp Ala Gly Gly 1380 1385 1390 GlyMet Ala Glu Gly Ala Val Gly Gln Met Arg Arg Arg Gly Leu Ala 1395 14001405 Ala Met Thr Pro Glu Thr Ala Leu Val Ala Leu Gly Gln Ala Leu Asp1410 1415 1420 His Asp Glu Thr Cys Val Thr Val Ala Asp Ile Asp Trp AspArg Phe 1425 1430 1435 1440 Thr Ala Asn Ser Leu Pro Gly Ser Arg Leu SerPro Leu Ile Ser Asp 1445 1450 1455 Ile Pro Glu Ala Arg Leu Ala Arg GluThr Thr Gly Leu Asp Thr Ala 1460 1465 1470 Thr Ala Ser Pro Asp Ser PheSer Ala Arg Leu Lys Ala Met Asp Thr 1475 1480 1485 Ala Glu Gln Glu ArgAla Leu Leu Asp Leu Val Arg Thr Tyr Ala Ala 1490 1495 1500 Thr Val LeuGly His Ser Thr Pro Thr Ala Val Arg Pro Glu Arg Ala 1505 1510 1515 1520Phe Arg Asp Leu Gly Phe Val Ser Val Ser Ala Val Glu Leu Arg Asn 15251530 1535 Arg Leu Asn Ala Val Thr Gly Leu Leu Leu Pro Thr Thr Leu IlePhe 1540 1545 1550 Asp Tyr Pro Thr Pro Ser Ala Leu Ala Gly Tyr Leu LysGlu Gln Leu 1555 1560 1565 Glu Glu Gly Ala Gly Gly Gln Arg Asp Ile AlaPro Pro Val Pro Ala 1570 1575 1580 Ser Arg Val Asp Val Asp Glu Pro IleAla Ile Val Gly Met Ala Cys 1585 1590 1595 1600 Arg Phe Pro Gly Gly ValGlu Ser Ala Glu Asp Leu Trp Glu Leu Val 1605 1610 1615 Ala Ser Gly ArgAsp Ala Val Gly Glu Phe Pro Val Asp Arg Gly Trp 1620 1625 1630 Asp ValGlu Ala Phe Tyr Asp Pro Glu Pro Gly Arg Ala Gly Ser Ser 1635 1640 1645Tyr Thr Arg Arg Gly Gly Phe Leu Glu Gly Ala Ala Glu Phe Asp Ala 16501655 1660 Gly Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu Ala Met Asp ProGln 1665 1670 1675 1680 Gln Arg Leu Met Leu Glu Val Ser Trp Glu Ala LeuGlu Arg Ala Gly 1685 1690 1695 Ile Asp Pro Ala Thr Leu Arg Gly Ser ThrThr Gly Val Phe Ala Gly 1700 1705 1710 Met Cys Ser Gln Asp Tyr Ala AspLeu Val Arg Arg Ala Thr Glu Asp 1715 1720 1725 Leu Glu Gly Tyr Ala MetThr Gly Leu Ser Ser Ser Val Thr Ser Gly 1730 1735 1740 Arg Val Ala TyrThr Leu Gly Leu Glu Gly Pro Ala Val Thr Val Asp 1745 1750 1755 1760 ThrAla Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys Gln Ala 1765 17701775 Leu Arg Ser Gly Glu Cys Ser Leu Ala Leu Ala Gly Gly Val Thr Val1780 1785 1790 Met Ser Thr Pro Gly Ala Phe Val Glu Phe Ser Arg Gln ArgGly Leu 1795 1800 1805 Ser Pro Asp Gly Arg Cys Lys Ala Tyr Gly Ser GlyAla Asp Gly Val 1810 1815 1820 Gly Trp Ala Glu Gly Val Gly Val Leu LeuVal Glu Arg Leu Ser Glu 1825 1830 1835 1840 Ala Glu Arg Arg Gly His ArgVal Leu Ala Val Val Arg Gly Ser Ala 1845 1850 1855 Val Asn Gln Asp GlyAla Ser Asn Gly Leu Thr Ala Pro Asn Gly Pro 1860 1865 1870 Ser Gln GlnArg Val Ile Arg Gln Ala Leu Ala Cys Ala Gly Leu Ser 1875 1880 1885 ValAla Asp Val Asp Val Val Glu Gly His Gly Thr Gly Thr Thr Leu 1890 18951900 Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Gly1905 1910 1915 1920 Arg Ser Gly Glu Arg Pro Val Trp Leu Gly Ser Val LysSer Asn Ile 1925 1930 1935 Gly His Ala Gln Ala Ala Ala Gly Val Ala GlyVal Ile Lys Met Val 1940 1945 1950 Met Ala Leu Arg Ala Gly Val Leu ProArg Thr Leu His Val Asp Glu 1955 1960 1965 Pro Ser Ser Gln Val Asp TrpSer Ser Gly Ser Val Arg Val Leu Ala 1970 1975 1980 Asp Glu Val Glu TrpPro Gly Val Glu Gly Arg Leu Arg Arg Ala Gly 1985 1990 1995 2000 Val SerAla Phe Gly Val Ser Gly Thr Asn Ala His Val Ile Leu Glu 2005 2010 2015Glu Ala Ser Gly Gly Ala Asp Gly Gly Ala Gly Arg Leu Gln Glu Leu 20202025 2030 Gly Pro Gly Val Val Ser Gly Ser Gly Val Val Pro Trp Val ValSer 2035 2040 2045 Ala Arg Ser Glu Leu Ala Leu Arg Gly Gln Ala Arg ArgLeu Arg Gly 2050 2055 2060 Val Val Ala Val Gly Gly Gly Ala Asp Gly ValGly Val Ser Pro Ala 2065 2070 2075 2080 Gly Val Gly Arg Ala Leu Val SerGlu Arg Ser Val Phe Glu His Arg 2085 2090 2095 Ala Val Val Val Ala GluAsp Arg Asp Glu Phe Leu His Ala Leu Asp 2100 2105 2110 Ala Leu Ala GluGly Ala Pro Thr Ala Gly Val Val Gln Gly Val Ala 2115 2120 2125 Gly ProAla Ala Asp Gly Lys Ile Ala Met Leu Phe Gly Gly Gln Gly 2130 2135 2140Thr His Trp Glu Gly Met Ala Gln Glu Leu Leu Gly Ser Ser Pro Val 21452150 2155 2160 Phe Ala Gln Gln Met Ser Asp Cys Ala Gln Ala Leu Glu ProTyr Leu 2165 2170 2175 Asp Trp Ser Leu Leu Asp Val Leu Arg Gly Ala ProAsp Ala Pro Pro 2180 2185 2190 Leu Gln Arg Val Asp Val Val Gln Pro ValLeu Phe Ala Val Met Val 2195 2200 2205 Ser Leu Ala Ala Leu Trp Arg SerTyr Gly Val His Pro Asp Ala Val 2210 2215 2220 Ala Gly His Ser Gln GlyGlu Ile Ala Ala Ala Tyr Val Ala Gly Ala 2225 2230 2235 2240 Leu Ser LeuAsp Asp Ala Ala Arg Val Thr Ala Leu Arg Ser Gln Ala 2245 2250 2255 LeuAla Ala Leu Ala Gly Gln Gly Ala Met Ala Ser Val Gly Leu Pro 2260 22652270 Val Glu Lys Leu Glu Pro Arg Leu Ala Thr Trp Gly Asp Arg Leu Val2275 2280 2285 Ile Ala Ala Val Asn Gly Ala Arg Ser Ala Val Val Ser GlyGlu Pro 2290 2295 2300 Glu Ala Val Asp Ala Leu Val Glu Glu Leu Ser HisGlu Asp Val Pro 2305 2310 2315 2320 Ala Arg Arg Leu Met Val Asp Trp AlaSer His Ser Pro Gln Val Glu 2325 2330 2335 Ala Ile Gln Gly Arg Leu LeuGlu Leu Leu Ala Pro Ile Arg Ala Arg 2340 2345 2350 Thr Gly Asp Val ProPhe Tyr Ser Thr Val Thr Gly Glu Arg Ile Asp 2355 2360 2365 Gly Thr GluLeu Asp Ala Asp Tyr Trp Tyr Arg Asn Leu Arg Gln Val 2370 2375 2380 ValArg Phe Arg Asp Ala Thr Gln Ala Leu Val Arg Ala Gly His Thr 2385 23902395 2400 Val Phe Ile Glu Ala Cys Pro His Pro Ala Val Ala Val Gly ValGln 2405 2410 2415 Glu Thr Leu Asp Glu Met Gly Asp Leu Asp Ser Leu ValVal Gly Ser 2420 2425 2430 Leu Arg Arg Gly Glu Gly Gly Leu Arg Arg PheLeu Met Ser Val Ala 2435 2440 2445 Glu Leu Phe Val Gly Gly Val Ala ValGlu Trp Ser Gly Val Phe Gly 2450 2455 2460 Ser Val Gly Arg Gly Val AlaGly Gly Cys Gly Val Glu Leu Pro Thr 2465 2470 2475 2480 Tyr Ala Phe GluArg Glu Arg Phe Trp Leu Asp Val Glu Gly Ala Pro 2485 2490 2495 Arg GlySer Gly Val Ser Gly Gln Trp Gly Gly Gln Leu Ser Glu Ala 2500 2505 2510Val Asp Thr Val Arg Gly Gly Met Leu Arg Asp Cys Leu Ala Gly Leu 25152520 2525 Asp Pro Ala Ala Gln Ala Glu Thr Val Leu Asp Leu Val Leu ThrHis 2530 2535 2540 Ala Ala Ala Val Leu Gly His Gly Thr Ala Asp Ala ValVal Pro Glu 2545 2550 2555 2560 Arg Ala Phe Arg Asp Leu Gly Phe Asp SerLeu Thr Ala Val Glu Leu 2565 2570 2575 Arg Asn Arg Leu Asn Thr Ala ThrGly Leu Arg Phe Pro Arg Thr Leu 2580 2585 2590 Val Phe Asp His Pro ArgPro Val Ala Leu Ala Ala His Ile His Glu 2595 2600 2605 Gln Leu Ser GlyGly Ser Pro Thr Thr Gly Thr Ala Leu Ala Leu Ala 2610 2615 2620 Leu ArgAla Pro Ala Pro Arg Val Asp Val Asp Glu Pro Ile Ala Ile 2625 2630 26352640 Val Gly Met Ala Cys Arg Phe Pro Gly Gly Val Glu Ser Ala Glu Asp2645 2650 2655 Phe Trp Glu Leu Ile Ala Ser Gly Arg Asp Ala Val Gly GluPhe Pro 2660 2665 2670 Val Asp Arg Gly Trp Asp Val Glu Ala Phe Tyr AspPro Glu Pro Gly 2675 2680 2685 Arg Ala Gly Thr Ser Tyr Thr Arg Cys GlyGly Phe Leu Gln Gly Ala 2690 2695 2700 Ala Glu Phe Asp Ala Gly Phe PheGly Ile Ser Pro Arg Glu Ala Leu 2705 2710 2715 2720 Ala Met Asp Pro GlnGln Arg Leu Met Leu Glu Val Ser Trp Glu Ala 2725 2730 2735 Leu Glu ArgAla Gly Ile Asp Pro Ala Thr Leu His Gly Ser Thr Thr 2740 2745 2750 GlyVal Phe Ala Gly Val Ser Gln Gln Asp Tyr Ala Glu Leu Leu Arg 2755 27602765 Arg Gly Thr Gln Asp His Glu Gly Tyr Ala Leu Thr Gly Val Ser Asn2770 2775 2780 Ser Val Val Ser Gly Arg Leu Ser Tyr Thr Phe Gly Phe GluGly Pro 2785 2790 2795 2800 Ala Val Thr Val Asp Thr Ala Cys Ser Ser SerLeu Val Ala Leu His 2805 2810 2815 Leu Ala Cys Gln Ala Leu Arg Ser GlyGlu Cys Ser Leu Ala Leu Ala 2820 2825 2830 Gly Gly Val Thr Val Met SerThr Pro Gly Ala Phe Val Glu Phe Ser 2835 2840 2845 Arg Gln Arg Gly LeuSer Pro Asp Gly Arg Cys Lys Ala Tyr Gly Ser 2850 2855 2860 Gly Ala AspGly Val Gly Trp Ala Glu Gly Val Gly Val Leu Leu Val 2865 2870 2875 2880Glu Arg Leu Ser Glu Ala Glu Arg Arg Gly His Arg Val Leu Ala Val 28852890 2895 Val Arg Gly Ser Ala Val Asn Gln Asp Gly Ala Ser Asn Gly LeuThr 2900 2905 2910 Ala Pro Asn Gly Pro Ser Gln Gln Arg Val Ile Arg GlnAla Leu Ala 2915 2920 2925 Cys Ala Gly Leu Ser Val Ala Asp Val Asp ValVal Glu Gly His Gly 2930 2935 2940 Thr Gly Thr Thr Leu Gly Asp Pro IleGlu Ala Gln Ala Leu Leu Ala 2945 2950 2955 2960 Thr Tyr Gly Gln Gly ArgSer Gly Glu Arg Pro Val Trp Leu Gly Ser 2965 2970 2975 Val Lys Ser AsnIle Gly His Ala Gln Ala Ala Ala Gly Val Ala Gly 2980 2985 2990 Val IleLys Met Val Met Ala Leu Asn His Glu Leu Leu Pro Thr Ser 2995 3000 3005Leu His Ile Asp Glu Pro Ser Pro His Ile Asp Trp Ser Ser Gly Gly 30103015 3020 Val Arg Leu Leu Thr Glu Pro Val Pro Trp Gln Gln Asn Gly ArgPro 3025 3030 3035 3040 Arg Arg Ala Gly Val Ser Ala Phe Gly Val Ser GlyThr Asn Ala His 3045 3050 3055 Val Ile Ile Glu Gln Ala Pro Val Glu AlaHis Val Ile Ser Glu Pro 3060 3065 3070 Val Pro Ala Glu Ala His Val IleVal Glu Gln Ala Pro Val Glu Ala 3075 3080 3085 Pro His Val Val Asp AlaThr Gly Pro Ala Asp Leu Thr Glu Pro Gln 3090 3095 3100 Glu Glu Ala AlaGlu Pro Glu Cys Val Ala Asp Ala Val Thr Glu Met 3105 3110 3115 3120 SerAla Glu Pro Glu Cys Val Ala Asp Ala Met Ser Glu Met Ser Ala 3125 31303135 Glu Cys Val Ala Glu Ala Val Ser Asp Lys Ser Ala Glu Pro Glu Cys3140 3145 3150 Val Ala Asp Ala Met Ser Asp Lys Pro Ala Leu Leu Pro IlePro Trp 3155 3160 3165 Leu Leu Ser Ala Lys Ser Glu Arg Ala Leu Arg GlyGln Ala Arg Arg 3170 3175 3180 Leu Arg Gln Phe Ala Ala Arg Ala Ser AspAla Arg Pro Ala Asp Val 3185 3190 3195 3200 Ala His Ala Leu Ala Ala GlnArg Ser Val Phe Asp His Arg Ala Val 3205 3210 3215 Val Val Ala Glu AspArg Asp Gly Phe Leu Gln Ala Leu Asp Ala Leu 3220 3225 3230 Ala Glu GlyArg Ser Ala Asp Gly Leu Ile Glu Gly Ser Val Gly Pro 3235 3240 3245 ArgGly Gly His Ser Gly Arg Arg Arg Gly Lys Thr Ala Met Leu Phe 3250 32553260 Ala Gly Gln Gly Thr Gln Arg Val Gly Met Gly Arg Gln Leu Tyr Ala3265 3270 3275 3280 Ala His Pro Ala Tyr Ala Asp Ala Leu Asp Gln Val LeuAla Glu Leu 3285 3290 3295 Asp Gly His Leu Asp Gln Pro Leu Arg Pro LeuIle His Ala Ser Ala 3300 3305 3310 Asp Leu Ala Asp Val Ala Asp Ala AlaAsp Val Leu Asp Arg Thr Arg 3315 3320 3325 Tyr Ala Gln Pro Ala Leu PheAla Val Gln Val Ala Leu Phe Arg His 3330 3335 3340 Leu Glu Arg Leu GlyVal Arg Ala Asp Phe Val Ala Gly His Ser Ile 3345 3350 3355 3360 Gly GluLeu Ala Ala Ala His Val Ala Gly Val Leu Pro Leu Ala Ala 3365 3370 3375Ala Cys Arg Leu Val Ala Ala Arg Gly Arg Leu Met Glu Gln Leu Ala 33803385 3390 Pro Gly Gly Ala Met Val Ala Val Arg Ala Ser Glu Ala Glu AlaArg 3395 3400 3405 Gln Ala Leu Asp Gly Arg Glu Ala Arg Val Ser Val AlaAla Val Asn 3410 3415 3420 Gly Pro Ala Ser Val Val Phe Ser Gly Ala GluAsp Glu Val Gly Asn 3425 3430 3435 3440 Met Ala Asp Trp Phe Ala Glu ArgGly Arg Arg Val Lys Arg Leu Arg 3445 3450 3455 Thr Gly His Ala Phe HisSer Pro Leu Met Asp Pro Met Leu Glu Glu 3460 3465 3470 Phe Gln Gln ValAla Ala Ser Leu Thr Tyr Ser Glu Pro Ala Ile Pro 3475 3480 3485 Met ValSer Thr Leu Thr Gly Asp Ile Val Ala Ala Gly Glu Leu Ser 3490 3495 3500Asp Pro Glu Tyr Trp Val Arg Gln Val Arg Arg Thr Val Arg Phe Gly 35053510 3515 3520 Asp Ala Ile Ser Arg Leu His Thr Asp Gly Val Arg Thr PheMet Glu 3525 3530 3535 Leu Gly Pro Asp Gly Thr Leu Ser Ala Leu Ala GluGlu Cys Leu Glu 3540 3545 3550 Ala Thr Ala Asp Ser His Pro Ala Asp AspAsp Thr Gly Thr Pro Gln 3555 3560 3565 Glu Asn Leu Leu Ile Pro Leu LeuArg Pro Asp Ser Pro Glu Pro Gly 3570 3575 3580 Thr Leu Leu Thr Gly LeuAla Arg Leu His Thr His Gly Ala Ala Ala 3585 3590 3595 3600 Val Asn TrpPro Ala Ala Leu Pro Glu Arg Asp Arg Ala Arg His Leu 3605 3610 3615 AspLeu Pro Thr Tyr Ala Phe Asp His His Arg Tyr Trp Val Asp Thr 3620 36253630 Ser Ala Gly His Pro Gly Asp Leu Ser Ala Ala Gly Leu Gly Thr Ala3635 3640 3645 Gly His Pro Leu Leu Gly Ser Ala Val Ala Leu Ala Glu SerGln Glu 3650 3655 3660 Leu Leu Phe Thr Gly Arg Leu Ser Leu Arg Thr HisPro Trp Leu Ala 3665 3670 3675 3680 Asp His Ala Ile Phe Gly Thr Val LeuLeu Pro Gly Thr Ala Ile Leu 3685 3690 3695 Glu Leu Ala Val Arg Ala GlyAsp Glu Val Asp Cys Gly Thr Val Glu 3700 3705 3710 Glu Leu Thr Leu ArgThr Pro Leu Val Leu Pro Glu Gln Gly Ser Val 3715 3720 3725 Ile Leu GlnLeu Ser Val Gly Ala Pro Gln Gly Pro Gln Thr Pro Glu 3730 3735 3740 GluPro Glu Arg Arg Thr Phe Ala Leu Tyr Ala Arg Glu Asp Asp Gly 3745 37503755 3760 Leu Ser Ser Ser Ser Ala Ala Ala Thr Gly Thr Glu Trp Thr CysHis 3765 3770 3775 Ala Thr Gly Val Leu Thr Gly Thr Ala Arg Pro Ala GluGlu His Thr 3780 3785 3790 Gln Glu Pro Trp Pro Pro Ala Asp Ala Ala ProVal Asp Leu Asp Gly 3795 3800 3805 Trp Tyr Glu Gln Leu Ala Gly Ala GlyLeu Gly Tyr Gly Pro Val Phe 3810 3815 3820 Gln Gly Leu Arg Glu Val TrpArg Arg Gly Asp Glu Val Phe Ala Val 3825 3830 3835 3840 Val Thr Leu ProGlu Ser Thr Glu Gly Gln Ala Ala Asp Ala Ala Arg 3845 3850 3855 Tyr AlaLeu His Pro Ala Leu Leu Asp Ala Ala Leu His Pro Val Val 3860 3865 3870Leu Arg His Glu Gly Asp Ala Ala Ala Asp Gly His Gly Trp Leu Pro 38753880 3885 Phe Ser Trp Thr Gly Val Thr Val Ala Ala Ser Gly Ala Ser ThrLeu 3890 3895 3900 His Val Arg Leu Thr Val Arg Thr Asp Glu Asp Ala ValGly Leu Leu 3905 3910 3915 3920 Ala Thr Asp Ala Ser Gly Arg Ile Val IleSer Ala Gly Ser Leu Ala 3925 3930 3935 Phe Arg Pro Val Ser Ala Glu GlnLeu Gln Ala Ala Arg Thr Gly Tyr 3940 3945 3950 His Asp His Leu Phe ArgIle Glu Trp Arg Pro Leu His Leu Pro Thr 3955 3960 3965 Thr Pro Ala ArgThr Ala Asp Trp Ala Leu Ile Gly Pro Gly Ala Arg 3970 3975 3980 Arg ThrAla Ala Val Leu Glu Arg Asn Gly Ala Ser Trp Gln Ala Tyr 3985 3990 39954000 Pro Asp Pro Ala Ala Leu Ala Glu Ala Leu Ala Ala Gly Ala Pro Ala4005 4010 4015 Pro Gly Met Val Val Ile Ser Cys Glu Pro Asp Gly Ala SerAla Pro 4020 4025 4030 Thr Asp Ser Ala Leu Thr Asp Ser Ala Leu Thr AspSer Ala Pro Ala 4035 4040 4045 Gly Ser Ala Pro Ala Asp Ser Thr Ala LeuAla Asp Ala Thr Arg Gln 4050 4055 4060 Ala Thr Thr Arg Val Leu Ala LeuLeu Gln Glu Trp Val Ala Asp Glu 4065 4070 4075 4080 Arg Leu Ala Ala CysArg Leu Ala Leu Leu Thr His Gly Ser Val Thr 4085 4090 4095 Ala Thr ProAsp Glu Pro Val Ser Asp Leu Ala His Ala Ala Val Trp 4100 4105 4110 GlyLeu Val Arg Ser Val Gln Thr Glu Asn Pro Asp Arg Phe Leu Leu 4115 41204125 Ala Asp Thr Asp Asp Thr Asp Ala Ser Arg Asn Ala Leu Pro Leu Leu4130 4135 4140 Ala Gly Glu Pro Gln Ile Ala Leu Arg Asn Gly Ala Val ArgIle Pro 4145 4150 4155 4160 Arg Met Thr Arg Val Pro Val Arg Gln Pro GlnPro Ser Thr Thr Asp 4165 4170 4175 Ala Asp Trp Asp Pro Glu Ala Thr ValLeu Ile Thr Gly Gly Thr Gly 4180 4185 4190 Val Leu Gly Arg Leu Val AlaArg His Leu Ala Thr Ala His Gly Val 4195 4200 4205 Arg His Leu Leu LeuAla Thr Arg Arg Gly Thr Ala Ala Asp Gly Ala 4210 4215 4220 Ala Asp LeuVal Ala Glu Leu Ala Gly Leu Gly Ala Glu Ala Thr Val 4225 4230 4235 4240Ala Ala Cys Asp Ile Gly Asp Arg Ala Ala Val Ala Ala Leu Leu Asp 42454250 4255 Gln Val Pro Ala Gln His Pro Leu Lys Ala Val Ile His Thr AlaGly 4260 4265 4270 Val Val Asp Asp Gly Ile Leu Thr Ser Leu Thr Pro GluArg Met Glu 4275 4280 4285 Ala Val Leu His Ala Lys Ala Phe Gly Ala AlaHis Leu His Asp Leu 4290 4295 4300 Thr Arg Asp Ala Gly Leu Thr Thr PheThr Val Phe Ser Ser Ala Ala 4305 4310 4315 4320 Ala Ser Phe Gly Ser ProGly Gln Gly Asn Tyr Thr Ala Ala Asn Ala 4325 4330 4335 Phe Leu Asp AlaLeu Met Gln His Arg His Thr Gln Ala Leu Pro Gly 4340 4345 4350 Arg SerLeu Ala Trp Gly Leu Trp Gly Glu Ala Asp Gly Met Thr Arg 4355 4360 4365Asn Leu Ala Gly Thr Asp Phe Ala Arg Met Ala Arg Gly Gly Leu Leu 43704375 4380 Pro Leu Ser Asn Ala Gln Gly Leu Ala Leu Leu Asp Thr Ala AspArg 4385 4390 4395 4400 Leu Gly Pro Phe Gly Asp Gly Leu Leu Leu Ala ThrArg Leu Asp Ala 4405 4410 4415 Ala Thr Leu His Ala Gln Ala Thr Ala GlyAla Leu Pro Arg Ile Leu 4420 4425 4430 His Gly Leu Ile Arg Ile Pro AlaArg Arg Ser Ala Asp His Gly Ile 4435 4440 4445 Ala Thr Asp Thr Pro AlaThr Leu Arg Glu Arg Leu Ala Gly Leu Thr 4450 4455 4460 Ile Pro Ala GlnArg Thr Gly Leu Leu Leu Glu Leu Val Arg Thr His 4465 4470 4475 4480 AlaAla Ala Val Leu Gly His Pro Thr Ser Ala Val Thr Ala Ala Asp 4485 44904495 Gly Ala Leu Pro Asp Asp Leu Val Pro Ala Asp Thr Glu Phe Arg Asp4500 4505 4510 Leu Gly Phe Asp Ser Leu Thr Ala Val Glu Leu Arg Asn ArgIle Asn 4515 4520 4525 Ala Val Thr Gly Leu Arg Leu Pro Ala Thr Leu IlePhe Asp Gln Pro 4530 4535 4540 Ser Pro Ala Ala Leu Ala Asp His Leu AlaThr Arg Leu Thr Ala Glu 4545 4550 4555 4560 Ala Gly Thr Pro Asp Glu ProAla Pro Ala Ala Ala Ala Ala Gly Ala 4565 4570 4575 Gly Ser Ala Gly SerAla Glu Thr Gly Gln Gln Arg Ser Thr Gly Ser 4580 4585 4590 Glu Lys GlnGln Thr Arg Gly Gly Thr Ser Thr Glu Thr Val Glu Ser 4595 4600 4605 LeuPhe Trp Ile Gly His Asp Thr Arg Arg Ile Glu Glu Ser Met Ala 4610 46154620 Leu Leu Ser Ala Ala Ser Phe Phe Arg Pro Ala Phe Thr Asp Pro Ser4625 4630 4635 4640 Asp Ile Pro Glu Pro Thr Phe Val Arg Leu Ala Gln GlyGlu Ala Arg 4645 4650 4655 Ala Gln Gly Glu Ala Leu Ala Arg Gly Glu ThrArg Pro Ala Leu Ile 4660 4665 4670 Cys Leu Pro Thr Val Ala Ala Val SerSer Val Tyr Gln Tyr Ser Arg 4675 4680 4685 Phe Ala Ala Gly Leu Asn GlyHis Arg Asp Val Trp Tyr Val Pro Ala 4690 4695 4700 Pro Gly Phe Leu GluGly Glu Pro Leu Pro Ser Gly Ile Gly Ala Val 4705 4710 4715 4720 Thr ArgMet Phe Ala Asp Ala Ile Val Arg Phe Thr Asp Gly Ala Pro 4725 4730 4735Phe Ala Leu Ala Gly His Ser Ala Gly Gly Trp Phe Val Tyr Ala Val 47404745 4750 Thr Ser His Leu Glu Arg Leu Gly Val Arg Pro Glu Ala Val ValThr 4755 4760 4765 Met Asp Ala Tyr Leu Pro Asp Asp Gly Ile Ala Pro ValAla Ser Ala 4770 4775 4780 Leu Thr Ser Glu Ile Phe Asp Arg Val Thr GlnPhe Val Asp Val Asp 4785 4790 4795 4800 Tyr Thr Arg Leu Val Ala Met GlyGly Tyr Phe Arg Ile Phe Ser Gly 4805 4810 4815 Trp Ser Pro Pro Asp IleThr Thr Pro Ala Leu Phe Leu Arg Gly Arg 4820 4825 4830 Asp Gly Glu GlnMet Pro Pro Pro Trp Gly Val Pro His Thr Val Leu 4835 4840 4845 Asp IleGln Gly Asn His Phe Thr Met Leu Glu Gln Phe Ala Asp Ser 4850 4855 4860Thr Ala Arg His Val Asp Glu Trp Leu Thr Glu Ile Ala Ser Val Arg 48654870 4875 4880 Arg 7 5532 PRT Streptomyces avermitilis 7 Met Asp Thr SerSer Glu Lys Leu Val Asp Ala Leu Arg Ala Ser Leu 1 5 10 15 Lys Ala AsnGln Thr Leu Arg Ala Arg Asn Glu Gln Leu Ala Ala Ala 20 25 30 Met Glu AlaSer Ser Glu Pro Ile Ala Ile Val Gly Met Ala Cys Arg 35 40 45 Phe Pro GlyGly Val Cys Ser Pro Glu Glu Leu Trp Glu Leu Val Ala 50 55 60 Ser Gly GlyAsp Ala Ile Gly Glu Phe Pro Ala Gly Arg Gly Trp Asp 65 70 75 80 Leu GluGly Leu Phe Asp Ser Asp Pro Asp Arg Ser Gly Thr Ser Tyr 85 90 95 Ala ArgTyr Gly Gly Phe Leu Tyr Glu Ala Gly Glu Phe Asp Ala Asp 100 105 110 PhePhe Gly Ile Ser Pro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln 115 120 125Arg Leu Leu Leu Glu Thr Ser Trp Glu Ala Phe Glu Arg Ala Gly Ile 130 135140 Asp Pro Leu Ser Met Arg Gly Ser Arg Thr Gly Val Phe Ala Gly Val 145150 155 160 Met Tyr His Asp Tyr Gly Ser Arg Leu Gly Thr Ile Pro Glu GlyPhe 165 170 175 Glu Gly Tyr Ile Gly Asn Gly Ser Gly Gly Ala Val Ala SerGly Arg 180 185 190 Val Ala Tyr Thr Leu Gly Leu Glu Gly Pro Ala Val SerVal Asp Thr 195 200 205 Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu AlaCys Gln Ser Leu 210 215 220 Arg Ser Gly Glu Cys Thr Leu Ala Leu Ala GlyGly Val Thr Val Met 225 230 235 240 Ser Thr Pro His Leu Phe Val Glu PheSer Arg Gln Arg Gly Leu Ser 245 250 255 Val Asp Gly Arg Cys Lys Ser PheAla Gly Gly Ala Asp Gly Thr Gly 260 265 270 Met Gly Glu Gly Val Gly MetLeu Leu Val Glu Arg Leu Ser Asp Ala 275 280 285 Val Arg Leu Gly His ArgVal Leu Ala Val Leu Arg Gly Ser Ala Val 290 295 300 Asn Gln Asp Gly AlaSer Asn Gly Leu Thr Ala Pro Asn Gly Pro Ala 305 310 315 320 Gln Glu ArgVal Ile Arg Gln Ala Leu Ala Asn Ala Gly Leu Ser Val 325 330 335 Ala AspVal Asp Val Val Glu Gly His Gly Thr Gly Thr Thr Leu Gly 340 345 350 AspPro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Arg Ala 355 360 365Gly Asn Arg Pro Leu Trp Leu Gly Ser Val Lys Ser Asn Ile Gly His 370 375380 Ala Gln Ala Ala Ala Gly Val Gly Gly Val Ile Lys Met Val Met Ala 385390 395 400 Leu Arg Glu Gly Val Leu Pro Arg Thr Leu His Val Asp Glu ProSer 405 410 415 Pro Gln Val Asp Trp Ser Ala Gly Ala Val Arg Leu Leu ThrGlu Ala 420 425 430 Val Pro Trp Pro Gly Asp Ala Ala Gly Arg Leu Arg ArgAla Gly Val 435 440 445 Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His ValIle Leu Glu Glu 450 455 460 Ala Pro Ala Ala Gly Gly Cys Val Ala Gly GlyGly Val Leu Glu Gly 465 470 475 480 Ala Pro Gly Leu Ala Ile Ser Val AlaGlu Ser Val Ala Ala Pro Val 485 490 495 Ala Val Ser Ala Pro Val Ala GluSer Val Pro Val Pro Val Pro Val 500 505 510 Pro Val Pro Val Pro Val SerAla Arg Ser Glu Ala Gly Leu Arg Ala 515 520 525 Gln Ala Glu Ala Leu ArgGln Tyr Val Ala Val Arg Pro Asp Val Ser 530 535 540 Leu Ala Asp Val GlyAla Gly Leu Ala Cys Gly Arg Ala Val Leu Glu 545 550 555 560 His Arg AlaVal Val Leu Ala Ala Asp Arg Glu Glu Leu Val Gln Gly 565 570 575 Leu GlyAla Leu Ala Ala Gly Glu Pro Asp Arg Arg Val Thr Thr Gly 580 585 590 HisAla Pro Gly Gly Asp Arg Gly Gly Val Val Phe Val Phe Pro Gly 595 600 605Gln Gly Gly Gln Trp Ala Gly Met Gly Val Arg Leu Leu Ala Ser Ser 610 615620 Pro Val Phe Ala Arg Arg Met Gln Ala Cys Glu Glu Ala Leu Ala Pro 625630 635 640 Trp Val Asp Trp Ser Val Val Asp Ile Leu Arg Arg Asp Ala GlyAsp 645 650 655 Ala Val Trp Glu Arg Ala Asp Val Val Gln Pro Val Leu PheSer Val 660 665 670 Met Val Ser Leu Ala Ala Leu Trp Arg Ser Tyr Gly IleGlu Pro Asp 675 680 685 Ala Val Leu Gly His Ser Gln Gly Glu Ile Ala AlaAla His Val Cys 690 695 700 Gly Ala Leu Ser Leu Lys Asp Ala Ala Lys ThrVal Ala Leu Arg Ser 705 710 715 720 Arg Ala Leu Ala Ala Val Arg Gly ArgGly Gly Met Ala Ser Val Pro 725 730 735 Leu Pro Ala Gln Glu Val Glu GlnLeu Ile Gly Glu Arg Trp Ala Gly 740 745 750 Arg Leu Trp Val Ala Ala ValAsn Gly Pro Arg Ser Thr Ala Val Ser 755 760 765 Gly Asp Ala Glu Ala ValAsp Glu Val Leu Ala Tyr Cys Ala Gly Thr 770 775 780 Gly Val Arg Ala ArgArg Ile Pro Val Asp Tyr Ala Ser His Cys Pro 785 790 795 800 His Val GlnPro Leu Arg Glu Glu Leu Leu Glu Leu Leu Gly Asp Ile 805 810 815 Ser ProGln Pro Ser Gly Val Pro Phe Phe Ser Thr Val Glu Gly Thr 820 825 830 TrpLeu Asp Thr Thr Thr Leu Asp Ala Ala Tyr Trp Tyr Arg Asn Leu 835 840 845His Gln Pro Val Arg Phe Ser Asp Ala Val Gln Ala Leu Ala Asp Asp 850 855860 Gly His Arg Val Phe Val Glu Val Ser Pro His Pro Thr Leu Val Pro 865870 875 880 Ala Ile Glu Asp Thr Thr Glu Asp Thr Ala Glu Asp Val Thr AlaIle 885 890 895 Gly Ser Leu Arg Arg Gly Asp Asn Asp Thr Arg Arg Phe LeuThr Ala 900 905 910 Leu Ala His Thr His Thr Thr Gly Ile Gly Thr Pro ThrThr Trp His 915 920 925 His His Tyr Thr His His His Thr His Pro His AsnHis His Leu Asp 930 935 940 Leu Pro Thr Tyr Pro Phe Gln Arg Gln His TyrTrp Leu Asp Ala Pro 945 950 955 960 Thr Gly Ala Gly Asp Val Ala Ala AlaGly Leu Glu Pro Ala Glu His 965 970 975 Pro Leu Leu Ala Ala Thr Val GlnLeu Ala Asp Thr Asp Gly Cys Leu 980 985 990 Leu Thr Gly Arg Leu Ser LeuArg Ser His Pro Trp Leu Gly Asp Tyr 995 1000 1005 Glu Val Gly Gly AlaVal Leu Leu Ser Gly Ser Ala Phe Val Glu Leu 1010 1015 1020 Ala Val GlnVal Gly Glu Arg Val Gly Cys Thr Arg Ile Glu Gln Leu 1025 1030 1035 1040Thr Val His Ala Pro Leu Val Val Pro Val Gly Gly Gly Val Ser Val 10451050 1055 Gln Val Gly Val Ala Ala Ala Asp Gly Glu Gly Arg Arg Leu ValSer 1060 1065 1070 Val Tyr Ala Arg Gly Gly Ser Ala Cys Gly Gly Gly GlyAla Ser Gly 1075 1080 1085 Gly Val Trp Thr Cys His Ala Ser Gly Val LeuVal Glu Ala Ala Ala 1090 1095 1100 Gly Gly Gly Val Val Val Asp Gly LeuAla Gly Val Trp Pro Pro Arg 1105 1110 1115 1120 Gly Ala Val Ala Val AspVal Asp Gly Val Arg Asp Arg Leu Ala Gly 1125 1130 1135 Ala Gly Cys ValLeu Gly Pro Val Phe Ser Gly Leu Arg Ala Val Trp 1140 1145 1150 Arg AspGly Gly Asp Leu Leu Ala Glu Val Cys Leu Pro Glu Glu Ala 1155 1160 1165Trp Gly Asp Ala Ala Gly Phe Gly Leu His Pro Ala Leu Leu Asp Gly 11701175 1180 Val Val Gln Pro Leu Ser Val Leu Leu Pro Gly Gly Thr Gly PheGly 1185 1190 1195 1200 Glu Gly Ala Gly Phe Gly Glu Gly Val Arg Val ProAla Val Trp Gly 1205 1210 1215 Gly Val Ser Leu His Arg Ala Gly Val ThrGly Val Arg Val Arg Val 1220 1225 1230 Trp Ala Val Gly Arg Gly Gly GlyArg Glu Ala Val Ser Val Val Val 1235 1240 1245 Gly Asp Glu Ala Gly ValPro Val Ala Ser Val Asp Arg Leu Glu Leu 1250 1255 1260 Arg Pro Val AspMet Gly Gln Leu Arg Ala Val Ser Val Ser Ala Gly 1265 1270 1275 1280 ArgArg Gly Ser Leu Tyr Ala Val Gln Trp Ala Glu Val Gly Pro Val 1285 12901295 Pro Val Cys Gly Gln Ala Trp Ala Trp His Glu Asp Val Gly Glu Ser1300 1305 1310 Gly Gly Gly Pro Val Pro Gly Val Val Val Leu Arg Cys ProAsp Ala 1315 1320 1325 Gly Ala Gly Gly Gly Gly Gly Gly Gly Val Gly GluVal Val Gly Gly 1330 1335 1340 Val Leu Gly Val Val Gln Gly Trp Leu GlyLeu Glu Arg Phe Ala Gly 1345 1350 1355 1360 Ser Arg Leu Val Val Val ThrArg Gly Ala Val Val Ala Gly Gln Glu 1365 1370 1375 Asp Gly Pro Val AspVal Val Gly Ala Ala Val Trp Gly Leu Val Arg 1380 1385 1390 Ser Ala GlnAla Glu His Pro Asp Arg Phe Val Leu Leu Asp Leu Asp 1395 1400 1405 ThrAsp Thr Asp Thr Gly Thr Asp Leu Asp Thr Gly Ala Gly Ala Gly 1410 14151420 Ala Gly Ala Gly Trp Gly Val Asp Gly Gly His Val Ala Ala Val Val1425 1430 1435 1440 Ala Cys Gly Glu Pro Gln Leu Ala Val Arg Gly Glu ArgVal Leu Ala 1445 1450 1455 Ala Arg Leu Thr Arg Leu Glu Ser Ser Val AspVal Pro Ala Gln Arg 1460 1465 1470 Ser Gly Asp Val Ala Gly Arg Glu ValLeu Pro Trp Leu Ser Gly Gly 1475 1480 1485 Ser Val Leu Val Thr Gly GlyThr Gly Val Leu Gly Ala Ala Val Ala 1490 1495 1500 Arg His Leu Ala GlyVal Cys Gly Val Arg Asp Leu Leu Leu Val Ser 1505 1510 1515 1520 Arg ArgGly Pro Asp Ala Pro Gly Ala Glu Gly Leu Arg Ala Glu Leu 1525 1530 1535Ala Ala Leu Gly Ala Glu Val Arg Ile Val Ala Cys Asp Val Gly Glu 15401545 1550 Arg Arg Glu Val Val Arg Leu Leu Glu Gly Val Pro Ala Gly CysPro 1555 1560 1565 Leu Thr Gly Val Val His Ala Ala Gly Val Leu Asp AspAla Thr Ile 1570 1575 1580 Ala Ser Leu Thr Pro Glu Arg Leu Gly Thr ValPhe Ala Ala Lys Val 1585 1590 1595 1600 Asp Ala Ala Leu Leu Leu Asp GluLeu Thr Arg Gly Met Glu Leu Ser 1605 1610 1615 Ala Phe Val Leu Phe SerSer Ala Ala Gly Ile Leu Gly Ser Ala Gly 1620 1625 1630 Gln Gly Asn TyrAla Ala Ala Asn Ala Ala Leu Asp Ala Leu Ala Tyr 1635 1640 1645 Arg ArgArg Ala Ala Gly Leu Pro Gly Val Ser Leu Ala Trp Gly Leu 1650 1655 1660Trp Glu Glu Ala Ser Gly Met Thr Gly His Leu Ala Gly Thr Asp His 16651670 1675 1680 Arg Arg Ile Ile Arg Ser Gly Leu His Pro Met Ser Thr ProAsp Ala 1685 1690 1695 Leu Ala Leu Phe Asp Ala Ala Leu Ala Leu Asp ArgPro Val Leu Leu 1700 1705 1710 Pro Ala Asp Leu Arg Pro Ala Pro Pro LeuPro Pro Leu Leu Gln Asp 1715 1720 1725 Leu Leu Pro Ala Thr Arg Arg ArgThr Thr Arg Thr Thr Thr Thr Gly 1730 1735 1740 Gly Ala Asp Asn Gly AlaGln Leu His Ala Arg Leu Ala Gly Gln Thr 1745 1750 1755 1760 His Glu GlnGln His Thr Thr Leu Leu Ala Leu Val Arg Ser His Ile 1765 1770 1775 AlaThr Val Leu Gly His Thr Thr Pro Asp Thr Ile Pro Pro Asp Arg 1780 17851790 Ala Phe Arg Asp Leu Gly Phe Asp Ser Leu Thr Ala Val Glu Leu Arg1795 1800 1805 Asn Arg Leu Ser Arg Thr Thr Gly Leu Arg Leu Pro Thr ThrLeu Ala 1810 1815 1820 Phe Asp His Pro Asn Pro Thr Thr Leu Thr His HisLeu His Thr Gln 1825 1830 1835 1840 Leu Leu Gly Ser Asp Ser Thr Ala SerIle Pro Ala Pro Arg Ala Ala 1845 1850 1855 Ala Val Pro Ala Asp Gln AspGlu Pro Val Ala Ile Ile Gly Met Ala 1860 1865 1870 Cys Arg Tyr Pro GlyGly Val Thr Ser Ala Glu Glu Leu Trp Glu Leu 1875 1880 1885 Leu Ala SerGly Arg Asp Thr Val Gly Glu Phe Pro Thr Asp Arg Gly 1890 1895 1900 TrpAsp Leu Glu Ala Leu Phe Asp Pro Glu Pro Gly Arg Pro Gly Thr 1905 19101915 1920 Ser Tyr Thr Arg Cys Gly Ser Phe Leu Tyr Asp Ala Gly Glu PheAsp 1925 1930 1935 Ala Gly Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu AlaMet Asp Pro 1940 1945 1950 Gln Gln Arg Leu Leu Leu Glu Ala Ser Trp GluAla Met Glu Gln Ala 1955 1960 1965 Gly Ile Asp Pro Thr Thr Val Arg GlySer Gln Thr Gly Val Phe Ala 1970 1975 1980 Gly Leu Ile Pro Gln Ala TyrGly Pro Arg Leu His Glu Asn Ala Ala 1985 1990 1995 2000 Ala Asp Thr GluGly Tyr Val Leu Thr Gly Thr Ser Gly Ser Val Ala 2005 2010 2015 Ser GlyArg Ile Ser Tyr Thr Phe Gly Phe Glu Gly Pro Ala Val Ser 2020 2025 2030Val Asp Thr Ala Cys Ser Ser Ser Leu Val Ala Leu His Leu Ala Cys 20352040 2045 Gln Ala Leu Arg Ala Gly Glu Cys Ser Met Ala Leu Ala Gly GlyVal 2050 2055 2060 Thr Val Met Ser Ser Pro Gly Ala Phe Val Glu Phe SerArg Gln Arg 2065 2070 2075 2080 Gly Leu Ala Ala Asp Gly His Cys Lys AlaPhe Ser Ala Ala Ala Asp 2085 2090 2095 Gly Thr Gly Trp Gly Glu Gly ValGly Met Leu Leu Val Glu Arg Leu 2100 2105 2110 Ser Asp Ala Arg Arg AsnGly His Arg Val Leu Ala Val Val Arg Gly 2115 2120 2125 Ser Ala Val AsnGln Asp Gly Ala Ser Asn Gly Leu Thr Ala Pro Asn 2130 2135 2140 Gly ProSer Gln Gln Arg Val Ile Arg Gln Ala Leu Ala Asn Ala Gly 2145 2150 21552160 Leu Ser Ala Gly Asp Val Asp Ala Val Glu Ala His Gly Thr Gly Thr2165 2170 2175 Thr Leu Gly Asp Pro Ile Glu Ala Gln Ala Leu Leu Ala ThrTyr Gly 2180 2185 2190 Gln Asp Arg Ala Gly Glu Gly Pro Leu Trp Leu GlySer Val Lys Ser 2195 2200 2205 Asn Val Gly His Thr Gln Ala Ala Ala GlyVal Ala Gly Val Ile Lys 2210 2215 2220 Met Val Met Ala Leu Arg Asn GlyLeu Leu Pro Arg Thr Leu His Val 2225 2230 2235 2240 Asp Glu Pro Ser ProHis Val Asp Trp Ser Ala Gly Ala Val Gln Leu 2245 2250 2255 Leu Thr GluThr Val Pro Trp Pro Gly Gly Glu Gly Arg Leu Arg Arg 2260 2265 2270 AlaGly Val Ser Ser Phe Gly Val Ser Gly Thr Asn Ala His Val Ile 2275 22802285 Leu Glu Glu Ala Pro Ala His Asn Ile Pro Ser Asp Thr Pro Ala Asp2290 2295 2300 Asp Val Pro Gly Gly Pro Pro Ala Gly Glu Asp Ala Gly SerGly Glu 2305 2310 2315 2320 Glu Ala Ala Ala Gly Ser Pro Gly Val Trp ProTrp Leu Val Ser Ala 2325 2330 2335 Lys Ser Gln Pro Ala Leu Arg Ala GlnAla Gln Ala Leu His Ala His 2340 2345 2350 Leu Thr Asp His Pro Gly LeuAsp Leu Ala Asp Val Gly Tyr Thr Leu 2355 2360 2365 Ala His Ala Arg AlaVal Phe Asp His Arg Ala Thr Leu Ile Ala Ala 2370 2375 2380 Asp Arg AspThr Phe Leu Gln Ala Leu Gln Ala Leu Ala Ala Gly Glu 2385 2390 2395 2400Pro His Pro Ala Val Ile His Ser Ser Ala Pro Gly Gly Thr Gly Thr 24052410 2415 Gly Glu Ala Ala Gly Lys Thr Ala Phe Ile Cys Ser Gly Gln GlyThr 2420 2425 2430 Gln Arg Pro Gly Met Ala His Gly Leu Tyr His Thr HisPro Val Phe 2435 2440 2445 Ala Ala Ala Leu Asn Asp Ile Cys Thr His LeuAsp Pro His Leu Asp 2450 2455 2460 His Pro Leu Leu Pro Leu Leu Thr GlnAsp Pro Asn Thr Gln Asp Thr 2465 2470 2475 2480 Thr Thr Leu Glu Glu AlaAla Ala Leu Leu Gln Gln Thr Pro Tyr Ala 2485 2490 2495 Gln Pro Ala LeuPhe Ala Phe Gln Val Ala Leu His Arg Leu Leu Thr 2500 2505 2510 Asp GlyTyr His Ile Thr Pro His Tyr Tyr Ala Gly His Ser Leu Gly 2515 2520 2525Glu Ile Thr Ala Ala His Leu Ala Gly Ile Leu Thr Leu Thr Asp Ala 25302535 2540 Thr Thr Leu Ile Thr Gln Arg Ala Thr Leu Met Gln Thr Met ProPro 2545 2550 2555 2560 Gly Thr Met Thr Thr Leu His Thr Thr Pro His HisIle Thr His His 2565 2570 2575 Ile Thr Ala His Glu Asn Asp Leu Ala IleAla Ala Ile Asn Thr Pro 2580 2585 2590 Thr Ser Leu Val Ile Ser Gly ThrPro His Thr Val Gln His Ile Thr 2595 2600 2605 Thr Leu Cys Gln Gln GlnGly Ile Lys Thr Lys Thr Leu Pro Thr Asn 2610 2615 2620 His Ala Phe HisSer Pro His Thr Asn Pro Ile Leu Asn Gln Leu His 2625 2630 2635 2640 GlnHis Thr Gln Thr Leu Thr Tyr His Pro Pro His Thr Pro Leu Ile 2645 26502655 Thr Ala Asn Thr Pro Pro Asp Gln Leu Leu Thr Pro His Tyr Trp Thr2660 2665 2670 Gln Gln Ala Arg Asn Thr Val Asp Ile Ala Thr Thr Thr GlnThr Leu 2675 2680 2685 His Gln His Gly Val Thr Thr Tyr Ile Glu Leu GlyPro Asp Asn Thr 2690 2695 2700 Leu Thr Thr Leu Thr His His Asn Leu ProAsn Thr Pro Thr Thr Thr 2705 2710 2715 2720 Leu Thr Leu Thr His Pro HisHis His Pro Gln Thr His Leu Leu Thr 2725 2730 2735 Asn Leu Ala Lys ThrThr Thr Thr Trp His Pro His His Tyr Thr His 2740 2745 2750 His His AsnGln Pro His Thr His Thr His Leu Asp Leu Pro Thr Tyr 2755 2760 2765 ProPhe Gln His His His Tyr Trp Leu Glu Ser Thr Gln Pro Gly Ala 2770 27752780 Gly Asn Val Ser Ala Ala Gly Leu Asp Pro Thr Glu His Pro Leu Leu2785 2790 2795 2800 Gly Ala Thr Leu Glu Leu Ala Glu Gly Asp Gly Cys LeuLeu Thr Gly 2805 2810 2815 Arg Leu Ser Leu Arg Thr His Pro Trp Leu AlaGly His Ala Val Gly 2820 2825 2830 Gly Val Val Leu Leu Pro Gly Thr AlaPhe Ala Glu Leu Ala Leu His 2835 2840 2845 Ala Gly Glu Ser Val Gly CysAsp His Val Asp Glu Leu Thr Leu His 2850 2855 2860 Thr Pro Leu Val IlePro Glu Val Gly Asp Val Thr Leu Gln Val Ala 2865 2870 2875 2880 Ile AlaAla Pro Asp Glu Ser Gly Arg Arg Met Met Thr Ile His Ser 2885 2890 2895Arg Gly Glu Gly Gly Ser Gly Gly Ala Asp Ala Ser Ala Ser Ala Trp 29002905 2910 Thr Arg His Ala Ala Gly Val Leu Ser Pro Ala Lys Asp Asp AspThr 2915 2920 2925 Ala Ser Tyr Glu Leu Leu Ala Gly Pro Trp Pro Pro ValGly Ala Thr 2930 2935 2940 Pro Val Asp Leu Asn Thr Ala Tyr Asp Gln MetAla Asp Ala Gly Phe 2945 2950 2955 2960 Ala Tyr Gly Leu Ala Phe Gln GlyLeu Arg Ala Ala Trp Arg Tyr Gly 2965 2970 2975 Asp Asp Ile Leu Val GluAla Arg Leu Pro Glu Glu Val Ser Gly Asp 2980 2985 2990 Ala Ala Ala TyrGly Leu His Pro Ala Leu Leu Asp Ala Ala Leu Gln 2995 3000 3005 Gly ThrGly Leu Leu Ser Val Ala Gly Pro Gly Thr Pro Val Val Pro 3010 3015 3020His Val Trp Asn Gly Leu Arg Phe Arg Thr His Gly Ala Val Ser Val 30253030 3035 3040 Arg Ala Cys Leu Ser Thr Leu Gly Ala Thr Gly Ala Ala ValCys Val 3045 3050 3055 Arg Ile Thr Asp Asp Thr Gly Val Pro Val Ala SerVal Asp Arg Leu 3060 3065 3070 Glu Leu Arg Pro Val Asp Met Gly Gln LeuArg Ala Val Ser Val Ser 3075 3080 3085 Ala Gly Arg Arg Gly Ser Leu TyrAla Val Gln Trp Ala Glu Val Gly 3090 3095 3100 Pro Val Pro Val Cys GlyGln Ala Trp Ala Trp His Glu Asp Val Gly 3105 3110 3115 3120 Glu Ser GlyGly Gly Pro Val Pro Gly Val Val Val Leu Arg Cys Pro 3125 3130 3135 AspAla Gly Ala Asp Gly Gly Gly Gly Gly Gly Val Gly Glu Val Val 3140 31453150 Gly Gly Val Leu Gly Val Val Gln Gly Trp Leu Gly Leu Glu Arg Phe3155 3160 3165 Ala Gly Ser Arg Leu Val Val Val Thr Arg Gly Ala Val ValAla Gly 3170 3175 3180 Pro Glu Asp Gly Pro Val Asp Val Val Gly Ala AlaVal Trp Gly Leu 3185 3190 3195 3200 Val Arg Ser Ala Gln Ala Glu His ProAsp Arg Phe Val Leu Leu Asp 3205 3210 3215 Leu Asp Thr Asp Leu Asp SerGly Ala Asp Ala Asp Ala Gly Asn Glu 3220 3225 3230 Ala Gly Met Gly SerGly Leu Asp Gly Gly Arg Val Ala Ala Val Val 3235 3240 3245 Ala Cys GlyGlu Pro Gln Leu Ala Val Arg Gly Glu Arg Val Leu Ala 3250 3255 3260 AlaArg Leu Thr Arg Leu Glu Ser Pro Val Asp Val Ser Gly Arg Glu 3265 32703275 3280 Val Leu Pro Trp Leu Ser Gly Gly Ser Val Leu Val Thr Gly GlyThr 3285 3290 3295 Gly Val Leu Gly Ala Ala Val Ala Arg His Leu Ala GlyVal Cys Gly 3300 3305 3310 Val Arg Asp Leu Leu Leu Val Ser Arg Arg GlyPro Asp Ala Pro Gly 3315 3320 3325 Ala Glu Gly Leu Arg Ala Glu Leu AlaAla Leu Gly Ala Glu Val Arg 3330 3335 3340 Ile Val Ala Cys Asp Val GlyGlu Arg Arg Glu Val Val Arg Leu Leu 3345 3350 3355 3360 Glu Gly Val ProAla Gly Cys Pro Leu Thr Gly Val Val His Ala Ala 3365 3370 3375 Gly ValLeu Asp Asp Ala Thr Ile Ala Ser Leu Thr Pro Glu Arg Leu 3380 3385 3390Gly Thr Val Phe Ala Ala Lys Val Asp Ala Ala Leu Leu Leu Asp Glu 33953400 3405 Leu Thr Arg Gly Met Glu Leu Ser Ala Phe Val Leu Phe Ser SerAla 3410 3415 3420 Ala Gly Ile Leu Gly Ser Ala Gly Gln Gly Asn Tyr AlaAla Ala Asn 3425 3430 3435 3440 Ala Ala Leu Asp Ala Leu Ala Tyr Arg ArgArg Ala Ala Gly Leu Pro 3445 3450 3455 Gly Val Ser Leu Ala Trp Gly LeuTrp Glu Glu Ala Ser Gly Met Thr 3460 3465 3470 Gly His Leu Ala Gly ThrAsp His Arg Arg Ile Ile Arg Ser Gly Leu 3475 3480 3485 His Pro Met SerThr Pro Asp Ala Leu Ala Leu Phe Asp Ala Ala Leu 3490 3495 3500 Ala LeuAsp Arg Pro Val Leu Leu Pro Ala Asp Leu Arg Pro Ala Pro 3505 3510 35153520 Pro Leu Pro Pro Leu Leu Gln Asp Leu Leu Pro Ala Thr Arg Arg Arg3525 3530 3535 Thr Thr Arg Thr Thr Thr Thr Gly Gly Ala Asp Asn Gly AlaGln Leu 3540 3545 3550 His Ala Arg Leu Ala Gly Gln Thr His Glu Gln GlnHis Thr Thr Leu 3555 3560 3565 Leu Ala Leu Val Arg Ser His Ile Ala ThrVal Leu Gly His Asn Ala 3570 3575 3580 Pro Glu Met Ile Pro Val Asp SerAla Phe Arg Asp Leu Gly Phe Asp 3585 3590 3595 3600 Ser Leu Thr Ala ValGlu Leu Arg Asn Arg Leu Gly Glu Ala Thr Gly 3605 3610 3615 Leu Arg LeuPro Thr Ser Leu Val Phe Asp Gln Pro Asn Ala Ala Thr 3620 3625 3630 LeuAla Arg His Leu Arg Arg Glu Leu Met Gly Asp Asp Ala Glu Gly 3635 36403645 Glu Thr Pro Ser Gln Val Ala Leu His Gln Val Ala Ala Asp Glu Pro3650 3655 3660 Ile Ala Ile Val Gly Met Ala Cys Arg Phe Pro Gly Gly ValCys Ser 3665 3670 3675 3680 Pro Glu Glu Leu Trp Glu Leu Val Ala Ser GlyGly Asp Ala Ile Gly 3685 3690 3695 Glu Phe Pro Ala Gly Arg Gly Trp AspLeu Glu Gly Leu Phe Asp Ser 3700 3705 3710 Asp Pro Asp Arg Ser Gly ThrSer Tyr Ala Arg Tyr Gly Gly Phe Leu 3715 3720 3725 Tyr Glu Ala Gly GluPhe Asp Ala Asp Phe Phe Gly Ile Ser Pro Arg 3730 3735 3740 Glu Ala LeuAla Met Asp Pro Gln Gln Arg Leu Leu Leu Glu Thr Ser 3745 3750 3755 3760Trp Glu Ala Phe Glu Arg Ala Gly Ile Asp Pro Leu Ser Met Arg Gly 37653770 3775 Ser Arg Thr Gly Val Phe Ala Gly Val Met Tyr His Asp Tyr AlaAla 3780 3785 3790 Arg Leu His His Val Pro Glu Gly Phe Glu Gly Leu IleAla Asn Gly 3795 3800 3805 Ser Ala Gly Ser Val Ala Thr Gly Arg Val AlaTyr Ser Phe Gly Leu 3810 3815 3820 Glu Gly Pro Ala Val Thr Val Asp ThrAla Cys Ser Ser Ser Leu Val 3825 3830 3835 3840 Ala Leu His Trp Ala AlaGln Ala Leu Arg Ala Gly Glu Cys Ser Met 3845 3850 3855 Ala Leu Ala GlyGly Val Thr Val Met Ser Ser Pro Gly Thr Phe Val 3860 3865 3870 Glu PheSer Arg Gln Arg Gly Leu Ala Ala Asp Gly Arg Cys Lys Ala 3875 3880 3885Tyr Ser Ala Ala Ala Asp Gly Thr Gly Trp Ala Glu Gly Val Gly Met 38903895 3900 Leu Leu Val Glu Arg Leu Ser Asp Ala Arg Arg Asn Gly His ArgVal 3905 3910 3915 3920 Leu Ala Val Val Arg Gly Ser Ala Val Asn Gln AspGly Ala Ser Asn 3925 3930 3935 Gly Leu Thr Ala Pro Asn Gly Pro Ser GlnGln Arg Val Ile Arg Gln 3940 3945 3950 Ala Leu Ala Asn Ala Gly Leu ThrPro Ala Asp Val Asp Ala Val Glu 3955 3960 3965 Gly His Gly Thr Gly ThrThr Leu Gly Asp Pro Ile Glu Ala Gln Ala 3970 3975 3980 Leu Leu Ala AlaTyr Gly Gln His Arg Pro His His Arg Pro Leu Trp 3985 3990 3995 4000 LeuGly Ser Leu Lys Ser Asn Ile Gly His Ala Gln Ala Ala Ala Gly 4005 40104015 Val Gly Gly Val Ile Lys Met Val Met Ala Leu Arg Asn Gly Leu Leu4020 4025 4030 Pro Gln Thr Leu His Val Asp Glu Pro Thr Pro Gln Val AspTrp Ser 4035 4040 4045 Thr Gly Ala Val Gln Leu Leu Thr Gln Pro Val ProTrp Pro Ala Asp 4050 4055 4060 Pro Ala Gly Arg Pro Arg His Ala Gly ValSer Ser Phe Gly Val Ser 4065 4070 4075 4080 Gly Thr Asn Ala His Val IleLeu Glu Glu Ala Pro Ala Ala Ala Gly 4085 4090 4095 Gly Ala Ala Gly GlyGly Val Ser Val Gly Ala Pro Asn Pro Ala Leu 4100 4105 4110 Pro Val AlaGlu Ser Glu Pro Val Pro Val Pro Val Pro Val Ser Ala 4115 4120 4125 ArgSer Glu Ala Gly Leu Arg Ala Gln Ala Gln Ala Leu Arg Gln Tyr 4130 41354140 Val Ala Ala Arg Pro Asp Met Ser Pro Ala Asp Ile Gly Ala Gly Leu4145 4150 4155 4160 Ala Arg Gly Arg Ala Val Leu Glu His Arg Ala Val IleLeu Ala Ala 4165 4170 4175 Asp Arg Glu Glu Leu Ala Gln Ala Leu Thr AlaLeu Ala Ala Gly Glu 4180 4185 4190 Pro His Pro His Ile Thr Thr Gly HisThr Arg Gly Ser Asp Arg Gly 4195 4200 4205 Gly Val Val Phe Val Phe ProGly Gln Gly Gly Gln Trp Ala Gly Met 4210 4215 4220 Gly Leu Thr Leu LeuThr Ser Ser Pro Val Phe Ala Glu His Ile Asp 4225 4230 4235 4240 Ala CysGlu Lys Ala Leu Thr Pro Trp Val Pro Trp Ser Leu Thr Asp 4245 4250 4255Ile Leu His Arg Asp Pro Asp Asp Pro Ala Trp Gln Gln Ala Asp Val 42604265 4270 Val Gln Pro Val Leu Phe Ser Ile Met Val Ser Leu Ala Ala LeuTrp 4275 4280 4285 Arg Ser Tyr Gly Ile Glu Pro Asp Ala Val Leu Gly HisSer Gln Gly 4290 4295 4300 Glu Ile Ala Ala Ala His Ile Cys Gly Ala LeuSer Leu Lys Asp Ala 4305 4310 4315 4320 Ala Lys Thr Val Ala Leu Arg SerGln Ala Leu Ala Ala Val Arg Gly 4325 4330 4335 Arg Gly Ala Met Val SerLeu Pro Leu Pro Ala Gln Asp Val Gln Gln 4340 4345 4350 Leu Ile Ser GluArg Trp Glu Gly Gln Leu Trp Val Ala Ala Leu Asn 4355 4360 4365 Gly ProHis Ser Thr Thr Val Ser Gly Asp Thr Thr Ala Val Glu Glu 4370 4375 4380Leu Leu Thr His Cys Ala Asp Thr Gly Leu Arg Ala Lys Arg Ile Pro 43854390 4395 4400 Val Asp Tyr Ala Ser His Cys Pro His Val Gln Pro Leu HisAsp Glu 4405 4410 4415 Leu Leu His Leu Leu Gly Asp Ile Thr Pro Gln ProSer Thr Met Pro 4420 4425 4430 Phe Phe Ser Thr Val Val Gly His Leu ValTrp Tyr Thr Thr Thr Leu 4435 4440 4445 Asp Ala Ala Tyr Trp Tyr Arg AsnLeu His Gln Pro Val Arg Phe Ser 4450 4455 4460 His Ala Ile Gln Thr LeuThr Asp Asp Gly His Arg Pro Phe Ile Glu 4465 4470 4475 4480 Ile Ser ProHis Pro Thr Leu Val Pro Ala Ile Glu Asp Thr Thr Glu 4485 4490 4495 AsnThr Thr Glu Asn Ile Thr Ala Thr Gly Ser Leu Arg Arg Gly Asp 4500 45054510 Asn Asp Thr His Arg Phe Leu Thr Ala Leu Ala His Thr His Thr Thr4515 4520 4525 Gly Ile Arg Thr Pro Thr Thr Trp His His His Tyr Thr GlnThr His 4530 4535 4540 Pro His Pro His Asn His His Leu Asp Leu Pro ThrTyr Pro Phe Gln 4545 4550 4555 4560 His Gln His Tyr Trp Leu Gln Pro ProThr Thr Thr Thr Asp Leu Thr 4565 4570 4575 Thr Thr Gly Leu Thr Pro ThrHis His Pro Leu Leu Thr Ala Thr Leu 4580 4585 4590 Thr Leu Ala Asn AsnAsn Thr Gln Leu Leu Thr Gly Arg Leu Ser Leu 4595 4600 4605 Arg Thr HisPro Trp Leu Thr Asp His Thr Val Val Gly Thr Thr Leu 4610 4615 4620 ValPro Gly Thr Ala Leu Leu Glu Leu Ala Leu Gln Ala Thr Thr Thr 4625 46304635 4640 Asp His Leu Glu Glu Leu Ala Leu His Thr Pro Leu Val Ile ProArg 4645 4650 4655 Glu Gly Ala Val Asp Val Gln Val His Ile Asn Pro ProAsp Asp Thr 4660 4665 4670 Asp Thr Arg Ser Leu Thr Ile Tyr Ser Arg SerGlu Asn Ala Pro Ala 4675 4680 4685 Ala Ala Pro Trp Arg His His Ala ThrAla Val Leu Gly Thr Lys Thr 4690 4695 4700 Ser Arg Ile Glu Thr Gly ArgSer His Asp Asp Leu Ser Met Trp Pro 4705 4710 4715 4720 Pro Ala Gly AlaVal Arg Cys Ala Asp Glu Glu Leu Ala Ala Leu Tyr 4725 4730 4735 Gly AspTyr Glu Ala Asn Gly Phe Val Tyr Gly Pro Ala Phe Arg Gly 4740 4745 4750Leu Thr Ala Ala Trp Arg Leu Gly Asp Glu Val Phe Ala Glu Val Arg 47554760 4765 Leu Pro Glu Gln Val His Gly Glu Ala Ser Ala Tyr Asn Leu HisPro 4770 4775 4780 Ala Leu Leu Asp Ala Ala Leu His Ala Ala Ala Phe AlaPro Ser Gly 4785 4790 4795 4800 Ser Leu Pro Gln Gly Ser Val Pro Phe SerPhe Thr Gly Val Thr Leu 4805 4810 4815 His Ala Ala Asn Ala Ser Ser LeuArg Val Arg Leu Ser Pro Ala Asp 4820 4825 4830 Pro Asn Ser Gly His AlaAla Val Ser Val Leu Val Thr Asp Asp Thr 4835 4840 4845 Gly Thr Pro ValAla Ser Val Glu Ala Leu Ala Val Arg Pro Leu Ala 4850 4855 4860 Ala AspGlu Leu Arg Ala Ala Glu Arg Ala Val Gln Arg Ala Glu Leu 4865 4870 48754880 Phe Asp Met Lys Trp Val Glu Val Pro Ser Asp Val Leu Val Ser Gly4885 4890 4895 Gly Ala Ser Val Val Val Leu Asp Gly Ala Asp Asp Leu ValGly Leu 4900 4905 4910 Ala Ala Glu Glu Asp Gly Val Pro Gly Val Val ValLeu Arg Cys Pro 4915 4920 4925 Asp Ala Gly Ala Asp Gly Gly Gly Gly GlyGly Gly Val Gly Glu Val 4930 4935 4940 Val Gly Gly Val Leu Gly Val ValGln Gly Trp Leu Gly Leu Glu Arg 4945 4950 4955 4960 Phe Ala Gly Ser ArgLeu Val Val Val Thr Arg Gly Ala Val Val Ala 4965 4970 4975 Gly Pro GluAsp Gly Pro Val Asp Gly Pro Val Asp Val Val Gly Ala 4980 4985 4990 AlaVal Trp Gly Leu Val Arg Ser Ala Gln Ala Glu His Pro Asp Arg 4995 50005005 Phe Val Leu Leu Asp Leu Asp Thr Asp Leu Asp Ser Gly Ala Asp Arg5010 5015 5020 Asp Ala Gly Asn Glu Ala Gly Met Gly Ser Gly Leu Asp GlyGly Arg 5025 5030 5035 5040 Val Ala Ala Val Val Ala Cys Gly Glu Pro GlnLeu Ala Val Arg Gly 5045 5050 5055 Glu Arg Val Leu Ala Ala Arg Leu ThrArg Leu Glu Ser Pro Val Asp 5060 5065 5070 Val Ser Gly Arg Glu Val LeuPro Trp Leu Ser Gly Gly Ser Val Leu 5075 5080 5085 Val Thr Gly Gly ThrGly Val Leu Gly Ala Ala Val Ala Arg His Leu 5090 5095 5100 Ala Gly ValCys Gly Val Arg Asp Leu Leu Leu Val Ser Arg Arg Gly 5105 5110 5115 5120Pro Asp Ala Pro Gly Ala Glu Gly Leu Arg Ala Glu Leu Ala Ala Leu 51255130 5135 Gly Ala Glu Val Arg Ile Val Ala Cys Asp Val Gly Glu Arg ArgGlu 5140 5145 5150 Val Val Arg Leu Leu Glu Gly Val Pro Ala Gly Cys ProLeu Thr Gly 5155 5160 5165 Val Val His Ala Ala Gly Val Leu Asp Asp AlaThr Ile Ala Ser Leu 5170 5175 5180 Thr Pro Glu Arg Leu Gly Thr Val PheAla Ala Lys Val Asp Ala Ala 5185 5190 5195 5200 Leu Leu Leu Asp Glu LeuThr Arg Gly Met Glu Leu Ser Ala Phe Val 5205 5210 5215 Leu Phe Ser SerAla Ala Gly Ile Leu Gly Ser Ala Gly Gln Gly Asn 5220 5225 5230 Tyr AlaAla Ala Asn Ala Ala Leu Asp Ala Leu Ala Tyr Arg Arg Arg 5235 5240 5245Ala Ala Gly Leu Pro Gly Val Ser Leu Ala Trp Gly Leu Trp Glu Glu 52505255 5260 Ala Ser Gly Met Thr Gly His Leu Ala Gly Thr Asp His Arg ArgIle 5265 5270 5275 5280 Ile Arg Ser Gly Leu His Pro Met Ser Thr Pro AspAla Leu Ala Leu 5285 5290 5295 Phe Asp Ala Ala Leu Ala Leu Asp Arg ProVal Leu Leu Pro Ala Asp 5300 5305 5310 Leu Arg Pro Ala Pro Pro Leu ProPro Leu Leu Gln Asp Leu Leu Pro 5315 5320 5325 Ala Thr Arg Arg Arg ThrThr Arg Thr Thr Thr Thr Gly Gly Ala Asp 5330 5335 5340 Asn Gly Ala GlnLeu His Gly Arg Leu Ala Gly Gln Thr His Glu Gln 5345 5350 5355 5360 GlnHis Thr Thr Leu Leu Ala Leu Val Arg Ser His Ile Ala Thr Val 5365 53705375 Leu Gly His Thr Thr Pro Asp Thr Ile Pro Pro Asp Arg Ala Phe Arg5380 5385 5390 Asp Leu Gly Phe Asp Ser Leu Thr Ala Val Glu Leu Arg AsnArg Leu 5395 5400 5405 Ser His Thr Thr Gly Leu Arg Leu Pro Thr Thr LeuAla Phe Asp His 5410 5415 5420 Pro Asn Pro Thr Thr Leu Thr His His LeuHis Thr Gln Leu Val Ser 5425 5430 5435 5440 Lys Gly Leu Thr Ala Ala AlaGlu Pro Asp Ala Ala Thr Thr Pro Pro 5445 5450 5455 Gly Leu Pro Ser LeuLeu Ser Glu Leu Glu Arg Leu Glu Ala Val Val 5460 5465 5470 Leu Ser SerThr Thr Ser Ser Ala Ala Pro Leu Asp Asp Gly Ala Arg 5475 5480 5485 ThrArg Leu Ala Ser Arg Leu His Ser Leu Ala Gln Lys Leu Asn Gly 5490 54955500 Asp Asp Thr Ala Pro Asp Leu Ala Glu Thr Ser Asp Glu Glu Met Phe5505 5510 5515 5520 Ala Leu Ile Asp Arg Glu Val Gly Phe Glu Ser Gln 55255530 8 3972 PRT Artificial Sequence Description of Artificial SequenceSynthetic protein; one amino acid is sustituted 8 Val Gln Arg Met AspGly Gly Glu Glu Pro Arg Pro Ala Ala Gly Glu 1 5 10 15 Val Leu Gly ValAla Asp Glu Ala Asp Gly Gly Val Val Phe Val Phe 20 25 30 Pro Gly Gln GlyPro Gln Trp Pro Gly Met Gly Arg Glu Leu Leu Asp 35 40 45 Ala Ser Asp ValPhe Arg Glu Ser Val Arg Ala Cys Glu Ala Ala Phe 50 55 60 Ala Pro Tyr ValAsp Trp Ser Val Glu Gln Val Leu Arg Asp Ser Pro 65 70 75 80 Asp Ala ProGly Leu Asp Arg Val Asp Val Val Gln Pro Thr Leu Phe 85 90 95 Ala Val MetIle Ser Leu Ala Ala Leu Trp Arg Ser Gln Gly Val Glu 100 105 110 Pro CysAla Val Leu Gly His Ser Leu Gly Glu Ile Ala Ala Ala His 115 120 125 ValSer Gly Gly Leu Ser Leu Ala Asp Ala Ala Arg Val Val Thr Leu 130 135 140Trp Ser Gln Ala Gln Thr Thr Leu Ala Gly Thr Gly Ala Leu Val Ser 145 150155 160 Val Ala Ala Thr Pro Asp Glu Leu Leu Pro Arg Ile Ala Pro Trp Thr165 170 175 Glu Asp Asn Pro Ala Arg Leu Ala Val Ala Ala Val Asn Gly ProArg 180 185 190 Ser Thr Val Val Ser Gly Ala Arg Glu Ala Val Ala Asp LeuVal Ala 195 200 205 Asp Leu Thr Ala Ala Gln Val Arg Thr Arg Met Ile ProVal Asp Val 210 215 220 Pro Ala His Ser Pro Leu Met Tyr Ala Ile Glu GluArg Val Val Ser 225 230 235 240 Gly Leu Leu Pro Ile Thr Pro Arg Pro SerArg Ile Pro Phe His Ser 245 250 255 Ser Val Thr Gly Gly Arg Leu Asp ThrArg Glu Leu Asp Ala Ala Tyr 260 265 270 Trp Tyr Arg Asn Met Ser Ser ThrVal Arg Phe Glu Pro Ala Ala Arg 275 280 285 Leu Leu Leu Gln Gln Gly ProLys Thr Phe Val Glu Met Ser Pro His 290 295 300 Pro Val Leu Thr Met GlyLeu Gln Glu Leu Ala Pro Asp Leu Gly Asp 305 310 315 320 Thr Thr Gly ThrAla Asp Thr Val Ile Met Gly Thr Leu Arg Arg Gly 325 330 335 Gln Gly ThrLeu Asp His Phe Leu Thr Ser Leu Ala Gln Leu Arg Gly 340 345 350 His GlyGlu Thr Ser Ala Thr Thr Val Leu Ser Ala Arg Leu Thr Ala 355 360 365 LeuSer Pro Thr Gln Gln Gln Ser Leu Leu Leu Asp Leu Val Arg Ala 370 375 380His Thr Met Ala Val Leu Asn Asp Asp Gly Asn Glu Arg Thr Ala Ser 385 390395 400 Asp Ala Gly Pro Ser Ala Ser Phe Ala His Leu Gly Phe Asp Ser Val405 410 415 Met Gly Val Glu Leu Arg Asn Arg Leu Ser Lys Ala Thr Gly LeuArg 420 425 430 Leu Pro Val Thr Leu Ile Phe Asp His Thr Thr Pro Ala AlaVal Ala 435 440 445 Ala Arg Leu Arg Thr Ala Ala Leu Gly His Leu Asp GluAsp Thr Ala 450 455 460 Pro Val Pro Asp Ser Pro Ser Gly His Gly Gly ThrAla Ala Ala Asp 465 470 475 480 Asp Pro Ile Ala Ile Ile Gly Met Ala CysArg Phe Pro Gly Gly Val 485 490 495 Arg Ser Pro Lys Asp Leu Trp Glu LeuAla Ala Ser Gly Gly Asp Ala 500 505 510 Ile Gly Pro Phe Pro Thr Asp ArgGly Trp Pro Thr Glu Gln Arg His 515 520 525 Ala Gln Asp Pro Thr Gln ProGly Thr Phe Tyr Pro Gln Gly Gly Gly 530 535 540 Phe Leu His Asp Ala AlaHis Phe Asp Ala Gly Phe Phe Gly Ile Ser 545 550 555 560 Pro Arg Glu AlaLeu Ala Met Asp Pro Gln Gln Arg Leu Leu Leu Glu 565 570 575 Thr Ser TrpGlu Ala Phe Glu Arg Ala Gly Ile Asp Pro Leu Ser Val 580 585 590 Arg GlySer Arg Thr Gly Val Phe Ala Gly Ala Leu Ser Phe Asp Tyr 595 600 605 GlyPro Arg Met Asp Thr Ala Ser Ser Glu Gly Ala Ala Asp Val Glu 610 615 620Gly His Ile Leu Thr Gly Thr Thr Gly Ser Val Leu Ser Gly Arg Ile 625 630635 640 Ala Tyr Ser Phe Gly Leu Glu Gly Pro Ala Ile Thr Val Asp Thr Gly645 650 655 Gly Ser Ala Ser Leu Val Thr Leu His Leu Ala Cys Gln Ser LeuArg 660 665 670 Ser Gly Glu Cys Thr Leu Ala Leu Ala Gly Gly Val Ser ValMet Ser 675 680 685 Thr Leu Gly Met Phe Ile Glu Phe Ser Arg Gln Arg GlyLeu Ser Val 690 695 700 Asp Gly Arg Cys Lys Ala Tyr Ser Ala Ala Ala AspGly Thr Gly Trp 705 710 715 720 Gly Glu Gly Val Gly Met Leu Leu Val GluArg Leu Ser Asp Ala Val 725 730 735 Arg Leu Gly His Arg Val Leu Ala ValVal Arg Gly Ser Ala Val Asn 740 745 750 Gln Asp Gly Ala Ser Asn Gly LeuThr Ala Pro Asn Gly Pro Ala Gln 755 760 765 Glu Arg Val Ile Arg Gln AlaLeu Ala Asn Ala Gly Leu Ser Val Ala 770 775 780 Asp Val Asp Val Val GluGly His Gly Thr Gly Thr Thr Leu Gly Asp 785 790 795 800 Pro Ile Glu AlaGln Ala Leu Leu Ala Thr Tyr Gly Gln Arg Ala Gly 805 810 815 Asp Arg ProLeu Trp Leu Gly Ser Leu Lys Ser Asn Ile Gly His Thr 820 825 830 Met AlaAla Ala Gly Val Gly Gly Val Ile Lys Met Val Met Ala Leu 835 840 845 ArgGlu Gly Val Leu Pro Arg Thr Leu His Val Asp Lys Pro Ser Pro 850 855 860Gln Val Asp Trp Ser Ala Gly Ala Val Arg Leu Leu Thr Glu Ala Val 865 870875 880 Pro Trp Pro Gly Asp Ala Ala Gly Arg Leu Arg Arg Ala Gly Val Ser885 890 895 Ser Phe Gly Ile Gly Gly Thr Asn Ala His Val Ile Leu Glu GluAla 900 905 910 Pro Ala Ala Gly Gly Cys Val Ala Gly Gly Gly Val Leu GluGly Ala 915 920 925 Pro Gly Leu Ala Ile Ser Val Ala Glu Ser Val Ala AlaPro Val Ala 930 935 940 Val Ser Ala Pro Val Ala Glu Ser Val Pro Val ProVal Pro Val Pro 945 950 955 960 Val Pro Val Pro Val Ser Ala Arg Ser GluAla Gly Leu Arg Ala Gln 965 970 975 Ala Glu Ala Leu Arg Gln Tyr Val AlaVal Arg Pro Asp Val Ser Leu 980 985 990 Ala Asp Val Gly Ala Gly Leu AlaCys Gly Arg Ala Val Leu Glu His 995 1000 1005 Arg Ala Val Val Leu AlaAla Asp Arg Glu Glu Leu Val Gln Gly Leu 1010 1015 1020 Gly Ala Leu AlaAla Gly Glu Pro Asp Arg Arg Val Thr Thr Gly His 1025 1030 1035 1040 AlaPro Gly Gly Asp Arg Gly Gly Val Val Phe Val Phe Pro Gly Gln 1045 10501055 Gly Gly Gln Trp Ala Gly Met Gly Val Arg Leu Leu Ala Ser Ser Pro1060 1065 1070 Val Phe Ala Arg Arg Met Gln Ala Cys Glu Glu Ala Leu AlaPro Trp 1075 1080 1085 Val Asp Trp Ser Val Val Asp Ile Leu Arg Arg AspAla Gly Asp Ala 1090 1095 1100 Val Trp Glu Arg Ala Asp Val Val Gln ProVal Leu Phe Ser Val Met 1105 1110 1115 1120 Val Ser Leu Ala Ala Leu TrpArg Ser Tyr Gly Ile Glu Pro Asp Ala 1125 1130 1135 Val Leu Gly His SerGln Gly Glu Ile Ala Ala Ala His Val Cys Gly 1140 1145 1150 Ala Leu SerLeu Lys Asp Ala Ala Lys Thr Val Ala Leu Arg Ser Arg 1155 1160 1165 AlaLeu Ala Ala Val Arg Gly Arg Gly Gly Met Ala Ser Val Pro Leu 1170 11751180 Pro Ala Gln Glu Val Glu Gln Leu Ile Gly Glu Arg Trp Ala Gly Arg1185 1190 1195 1200 Leu Trp Val Ala Ala Val Asn Gly Pro Arg Ser Thr AlaVal Ser Gly 1205 1210 1215 Asp Ala Glu Ala Val Asp Glu Val Leu Ala TyrCys Ala Gly Thr Gly 1220 1225 1230 Val Arg Ala Arg Arg Ile Pro Val AspTyr Ala Ser His Cys Pro His 1235 1240 1245 Val Gln Pro Leu Arg Glu GluLeu Leu Glu Leu Leu Gly Asp Ile Ser 1250 1255 1260 Pro Gln Pro Ser GlyVal Pro Phe Phe Ser Thr Val Glu Gly Thr Trp 1265 1270 1275 1280 Leu AspThr Thr Thr Leu Asp Ala Ala Tyr Trp Tyr Arg Asn Leu His 1285 1290 1295Gln Pro Val Arg Phe Ser Asp Ala Val Gln Ala Leu Ala Asp Asp Gly 13001305 1310 His Arg Val Phe Val Glu Val Ser Pro His Pro Thr Leu Val ProAla 1315 1320 1325 Ile Glu Asp Thr Thr Glu Asp Thr Ala Glu Asp Val ThrAla Ile Gly 1330 1335 1340 Ser Leu Arg Arg Gly Asp Asn Asp Thr Arg ArgPhe Leu Thr Ala Leu 1345 1350 1355 1360 Ala His Thr His Thr Thr Gly IleGly Thr Pro Thr Thr Trp His His 1365 1370 1375 His Tyr Thr His His HisThr His Pro His Pro His Thr His Leu Asp 1380 1385 1390 Leu Pro Thr TyrPro Phe Gln His Gln His Tyr Trp Leu Glu Ser Ser 1395 1400 1405 Gln ProGly Ala Gly Ser Gly Ser Gly Ala Gly Ala Gly Ser Gly Ala 1410 1415 1420Gly Ser Gly Arg Ala Gly Thr Ala Gly Gly Thr Ala Glu Val Glu Ser 14251430 1435 1440 Arg Phe Trp Asp Ala Val Ala Arg Gln Asp Leu Glu Thr ValAla Thr 1445 1450 1455 Thr Leu Ala Val Pro Pro Ser Ala Gly Leu Asp ThrVal Val Pro Ala 1460 1465 1470 Leu Ser Ala Trp His Arg His Gln His AspGln Ala Arg Ile Asn Thr 1475 1480 1485 Trp Thr Tyr Gln Glu Thr Trp LysPro Leu Thr Leu Pro Thr Thr His 1490 1495 1500 Gln Pro His Gln Thr TrpLeu Ile Ala Ile Pro Glu Thr Gln Thr His 1505 1510 1515 1520 His Pro HisIle Thr Asn Ile Leu Thr Asn Leu His His His Gly Ile 1525 1530 1535 ThrPro Ile Pro Leu Thr Leu Asn His Thr His Thr Asn Pro Gln His 1540 15451550 Leu His His Thr Leu His His Thr Arg Gln Gln Ala Gln Asn His Thr1555 1560 1565 Thr Gly Ala Ile Thr Gly Leu Leu Ser Leu Leu Ala Leu AspGlu Thr 1570 1575 1580 Pro His Pro His His Pro His Thr Pro Thr Gly ThrLeu Leu Asn Leu 1585 1590 1595 1600 Thr Leu Thr Gln Thr His Thr Gln ThrHis Pro Pro Thr Pro Leu Trp 1605 1610 1615 Tyr Ala Thr Thr Asn Ala ThrThr Thr His Pro Asn Asp Pro Leu Thr 1620 1625 1630 His Pro Thr Gln AlaGln Thr Trp Gly Leu Ala Arg Thr Thr Leu Leu 1635 1640 1645 Glu His ProThr His Thr Ala Gly Ile Ile Asp Leu Pro Thr Thr Pro 1650 1655 1660 ThrPro His Thr Leu Gln His Leu Thr Gln Thr Leu Thr Gln Pro His 1665 16701675 1680 His Gln Thr Gln Leu Ala Ile Arg Thr Thr Gly Thr His Thr ArgArg 1685 1690 1695 Leu Thr Pro Thr Thr Leu Thr Pro Thr His Gln Pro ProThr Pro Thr 1700 1705 1710 Pro His Gly Thr Thr Leu Ile Thr Gly Gly ThrGly Ala Leu Ala Thr 1715 1720 1725 His Leu Thr His His Leu Thr Thr HisGln Pro Thr Gln His Leu Leu 1730 1735 1740 Leu Thr Ser Arg Thr Gly ProHis Thr Pro His Ala Gln His Leu Thr 1745 1750 1755 1760 Thr Gln Leu GlnGln Lys Gly Ile His Leu Thr Ile Thr Thr Cys Asp 1765 1770 1775 Thr SerAsn Pro Asp Gln Leu Gln Gln Leu Leu Asn Thr Ile Pro Pro 1780 1785 1790Gln His Pro Leu Thr Thr Val Ile His Thr Ala Gly Ile Leu Asp Asp 17951800 1805 Ala Thr Leu Thr Asn Leu Thr Pro Thr Gln Leu Asn Asn Val LeuArg 1810 1815 1820 Ala Lys Ala His Ser Ala His Leu Leu His Gln Leu ThrGln His Thr 1825 1830 1835 1840 Pro Leu Thr Ala Phe Val Leu Tyr Ser SerAla Ala Ala Thr Phe Gly 1845 1850 1855 Ala Pro Gly Gln Ala Asn Tyr AlaAla Ala Asn Ala Tyr Leu Asp Ala 1860 1865 1870 Leu Ala His His Arg HisThr His His Leu Pro Ala Thr Ser Ile Ala 1875 1880 1885 Trp Gly Thr TrpGln Gly Asn Gly Leu Ala Asp Ser Asp Lys Ala Arg 1890 1895 1900 Ala TyrLeu Asp Arg Arg Gly Phe Arg Pro Met Ser Pro Glu Leu Ala 1905 1910 19151920 Thr Ala Ala Val Thr Gln Ala Ile Ala Asp Thr Glu Arg Pro Tyr Val1925 1930 1935 Val Ile Ala Asp Ile Asp Trp Ser Lys Ile Glu His Thr SerGln Thr 1940 1945 1950 Ser Asp Leu Val Ser Ala Ala Arg Glu Arg Glu ProAla Val Gln Arg 1955 1960 1965 Pro Thr Pro Pro Ala Glu Leu His Lys ThrLeu Ala His Gln Thr Ser 1970 1975 1980 Ala Asp Gln Arg Ala Ala Leu LeuGlu Leu Val Arg Asp His Val Ala 1985 1990 1995 2000 Ala Val Leu Arg HisAla Asp Pro Lys Ala Ile Ala Pro Asp Gln Ser 2005 2010 2015 Phe Arg AlaLeu Gly Phe Asp Ser Leu Thr Ala Val Glu Phe Arg Asn 2020 2025 2030 LeuLeu Ile Lys Ala Thr Gly Leu Arg Leu Pro Val Ser Leu Val Phe 2035 20402045 Asp His Pro Thr Pro Ala Lys Leu Ala Val His Leu Gln Asn Gln Leu2050 2055 2060 Arg Gly Thr Ala Ala Glu Ser Ala Pro Ser Ala Ala Ala ValThr Ala 2065 2070 2075 2080 Glu Ala Ser Val Thr Glu Pro Ile Ala Ile ValGly Met Ala Cys Arg 2085 2090 2095 Phe Pro Gly Gly Val Thr Ser Ala AspAsp Phe Trp Asp Leu Ile Ser 2100 2105 2110 Ser Glu Gln Asp Ala Ile GlyGly Phe Pro Thr Asp Arg Gly Trp Asp 2115 2120 2125 Leu Asp Thr Leu TyrAsp Pro Asp Pro Asp His Pro Gly Thr Cys Tyr 2130 2135 2140 Thr Arg AsnGly Gly Phe Leu Tyr Asp Ala Gly His Phe Asp Ala Glu 2145 2150 2155 2160Phe Phe Gly Ile Ser Pro Arg Glu Ala Leu Ala Met Asp Pro Gln Gln 21652170 2175 Arg Leu Leu Leu Glu Thr Ala Trp Glu Thr Ile Glu His Ala GlyIle 2180 2185 2190 Asn Pro His Thr Leu His Gly Thr Pro Thr Gly Val PheThr Gly Thr 2195 2200 2205 Asn Gly Gln Asp Tyr Ala Leu Arg Val His AsnAla Gly Gln Ser Thr 2210 2215 2220 Asp Gly Phe Ala Leu Thr Gly Thr AlaGly Ser Val Ile Ser Gly Arg 2225 2230 2235 2240 Ile Ser Tyr Thr Phe GlyPhe Glu Gly Pro Ala Val Ser Val Asp Thr 2245 2250 2255 Ala Cys Ser SerSer Leu Val Ala Leu His Leu Ala Cys Gln Ala Leu 2260 2265 2270 Arg AlaGly Glu Cys Ser Met Ala Leu Ala Gly Gly Val Thr Val Met 2275 2280 2285Ser Ser Pro Gly Ala Phe Val Glu Phe Ser Arg Gln Arg Gly Leu Ala 22902295 2300 Ala Asp Gly His Cys Lys Ala Phe Ser Ala Ala Ala Asp Gly ThrGly 2305 2310 2315 2320 Trp Gly Glu Gly Val Gly Met Leu Leu Val Glu ArgLeu Ser Asp Ala 2325 2330 2335 His Arg Asn Gly His Arg Val Leu Ala ValVal Arg Gly Ser Ala Val 2340 2345 2350 Asn Gln Asp Gly Ala Ser Asn GlyLeu Thr Ala Pro Asn Gly Pro Ser 2355 2360 2365 Gln Gln Arg Val Ile ArgGln Ala Leu Ala Asn Ala Gly Leu Ser Ala 2370 2375 2380 Gly Asp Val AspAla Val Glu Ala His Gly Thr Gly Thr Thr Leu Gly 2385 2390 2395 2400 AspPro Ile Glu Ala Gln Ala Leu Leu Ala Thr Tyr Gly Gln Asp Arg 2405 24102415 Ala Gly Glu Gly Pro Leu Trp Leu Gly Ser Val Lys Ser Asn Val Gly2420 2425 2430 His Thr Gln Ala Ala Ala Gly Val Ala Gly Val Ile Lys MetVal Met 2435 2440 2445 Ala Leu Arg His Gly Leu Leu Pro Arg Thr Leu HisVal Asp Glu Pro 2450 2455 2460 Ser Pro His Val Asp Trp Ser Ala Gly AlaVal Gln Leu Leu Thr Glu 2465 2470 2475 2480 Thr Val Pro Trp Pro Gly GlyGlu Gly Arg Leu Arg Arg Ala Gly Val 2485 2490 2495 Ser Ser Phe Gly ValSer Gly Thr Asn Ala His Val Ile Leu Glu Glu 2500 2505 2510 Ala Pro AlaAsp Asp Val Pro Gly Gly Pro Pro Ala Gly Glu Gly Asp 2515 2520 2525 AlaGly Ser Asp Asp Glu Ala Ala Ala Gly Ser Pro Gly Val Trp Pro 2530 25352540 Trp Leu Val Ser Ala Lys Ser Gln Pro Ala Leu Arg Ala Gln Ala Gln2545 2550 2555 2560 Ala Leu His Ala His Leu Thr Asp His Pro Gly Leu AspLeu Ala Asp 2565 2570 2575 Val Gly Tyr Thr Leu Ala His Ala Arg Ala ValPhe Asp His Arg Ala 2580 2585 2590 Thr Leu Ile Ala Ala Asp Arg Asp ThrPhe Leu Gln Ala Leu Gln Ala 2595 2600 2605 Leu Ala Ala Gly Glu Pro HisPro Ala Val Ile His Ser Ser Ala Pro 2610 2615 2620 Gly Gly Thr Gly ThrGly Glu Ala Ala Gly Lys Thr Ala Phe Ile Cys 2625 2630 2635 2640 Ser GlyGln Gly Thr Gln Arg Pro Gly Met Ala His Gly Leu Tyr His 2645 2650 2655Thr His Pro Val Phe Ala Ala Ala Leu Asn Asp Ile Cys Thr His Leu 26602665 2670 Asp Pro His Leu Asp His Pro Leu Leu Pro Leu Leu Thr Gln AsnAsp 2675 2680 2685 Asn Asp Asn Glu Asp Ala Ala Ala Leu Leu Gln Gln ThrArg Tyr Ala 2690 2695 2700 Gln Pro Ala Leu Phe Ala Phe Gln Val Ala LeuHis Arg Leu Leu Thr 2705 2710 2715 2720 Asp Gly Tyr His Ile Thr Pro HisTyr Tyr Ala Gly His Ser Leu Gly 2725 2730 2735 Glu Ile Thr Ala Ala HisLeu Ala Gly Ile Leu Thr Leu Thr Asp Ala 2740 2745 2750 Thr Thr Leu IleThr Gln Arg Ala Thr Leu Met Gln Thr Met Pro Pro 2755 2760 2765 Gly ThrMet Thr Thr Leu His Thr Thr Pro His His Ile Thr His His 2770 2775 2780Leu Thr Ala His Glu Asn Asp Leu Ala Ile Ala Ala Ile Asn Thr Pro 27852790 2795 2800 Thr Ser Leu Val Ile Ser Gly Thr Pro His Thr Val Gln HisIle Thr 2805 2810 2815 Thr Leu Cys Gln Gln Gln Gly Ile Lys Thr Lys ThrLeu Pro Thr Asn 2820 2825 2830 His Ala Phe His Ser Pro His Thr Asn ProIle Leu Asn Gln Leu His 2835 2840 2845 Gln His Thr Gln Thr Leu Thr TyrHis Pro Pro His Thr Pro Leu Ile 2850 2855 2860 Thr Ala Asn Thr Pro ProAsp Gln Leu Leu Thr Pro His Tyr Trp Thr 2865 2870 2875 2880 Gln Gln AlaArg Asn Thr Val Asp Tyr Ala Thr Thr Thr Gln Thr Leu 2885 2890 2895 HisGln His Gly Val Thr Thr Tyr Ile Glu Leu Gly Pro Asp Asn Thr 2900 29052910 Leu Thr Thr Leu Thr His His Asn Leu Pro Asn Pro Pro Thr Thr Thr2915 2920 2925 Leu Thr Leu Thr His Pro His His His Pro Gln Thr His LeuLeu Thr 2930 2935 2940 Asn Leu Ala Lys Thr Thr Thr Thr Trp His Pro HisHis Tyr Thr His 2945 2950 2955 2960 His Asp Asn Gln Pro His Thr His ThrHis Leu Asp Leu Pro Thr Tyr 2965 2970 2975 Pro Phe Gln His His His TyrTrp Leu Glu Ser Thr Gln Pro Gly Ala 2980 2985 2990 Gly Asn Val Ser AlaAla Gly Leu Asp Pro Thr Glu His Pro Leu Leu 2995 3000 3005 Gly Ala ThrLeu Glu Leu Ala Thr Asp Gly Gly Ala Leu Leu Ala Gly 3010 3015 3020 ArgLeu Ser Leu Arg Ser His Pro Trp Leu Ala Asp His Ala Val Gly 3025 30303035 3040 Gly Thr Val Leu Leu Ser Gly Ala Thr Phe Leu Glu Leu Ala LeuHis 3045 3050 3055 Ala Gly Thr Tyr Val Gly Cys Asp Arg Val Asp Glu LeuThr Leu His 3060 3065 3070 Ala Pro Leu Val Val Pro Val Asp Gly Gly ValSer Val Gln Val Gly 3075 3080 3085 Val Ala Ala Ala Asp Gly Glu Gly ArgArg Leu Val Ser Val Tyr Ala 3090 3095 3100 Arg Gly Gly Ser Ala Cys GlyGly Gly Gly Ala Ser Gly Gly Val Trp 3105 3110 3115 3120 Thr Cys His AlaSer Gly Val Leu Val Glu Ala Ala Ala Gly Gly Val 3125 3130 3135 Val ValAsp Gly Leu Ala Gly Val Trp Pro Pro Arg Gly Ala Val Ala 3140 3145 3150Val Asp Val Asp Gly Val Arg Asp Arg Leu Ala Gly Ala Gly Cys Val 31553160 3165 Leu Gly Pro Val Phe Ser Gly Leu Arg Ala Val Trp Arg Asp GlyGly 3170 3175 3180 Asp Leu Leu Ala Glu Val Cys Leu Pro Glu Glu Ala TrpGly Asp Ala 3185 3190 3195 3200 Ala Gly Phe Gly Leu His Pro Ala Leu LeuAsp Gly Val Val Gln Pro 3205 3210 3215 Leu Ser Val Leu Leu Pro Gly GlyThr Gly Phe Gly Glu Gly Ala Gly 3220 3225 3230 Phe Gly Glu Gly Val ArgVal Pro Ala Val Trp Gly Gly Val Ser Leu 3235 3240 3245 His Arg Ala GlyVal Thr Gly Val Arg Val Arg Val Ser Ala Val Gly 3250 3255 3260 Arg GlyGly Gly Arg Glu Ala Val Ser Val Val Val Gly Asp Glu Ala 3265 3270 32753280 Gly Val Pro Val Ala Ser Val Asp Arg Leu Glu Leu Arg Pro Val Asp3285 3290 3295 Met Gly Gln Leu Arg Ala Val Ser Val Ser Ala Gly Arg ArgGly Ser 3300 3305 3310 Leu Tyr Ala Val Gln Trp Ala Glu Val Gly Pro ValPro Val Cys Gly 3315 3320 3325 Gln Ala Trp Ala Trp His Glu Asp Val GlyGlu Ser Gly Gly Gly Pro 3330 3335 3340 Val Pro Gly Val Val Val Leu ArgCys Pro Asp Ala Gly Ala Gly Gly 3345 3350 3355 3360 Gly Gly Gly Gly GlyGly Gly Gly Gly Val Gly Glu Val Val Gly Gly 3365 3370 3375 Val Leu GlyVal Val Gln Gly Trp Leu Gly Leu Glu Arg Phe Ala Gly 3380 3385 3390 SerArg Leu Val Val Val Thr Arg Gly Ala Val Val Ala Gly Pro Glu 3395 34003405 Asp Gly Pro Val Asp Val Val Gly Ala Ser Val Trp Gly Leu Val Arg3410 3415 3420 Ser Ala Gln Ala Glu His Pro Asp Arg Phe Val Leu Leu AspLeu Asp 3425 3430 3435 3440 Thr Asp Thr Gly Thr Asp Leu Asp Thr Gly AlaGly Ala Gly Trp Gly 3445 3450 3455 Val Asp Gly Gly Arg Val Ala Ala ValVal Ala Cys Gly Glu Pro Gln 3460 3465 3470 Leu Ala Val Arg Gly Glu ArgLeu Leu Ala Ala Arg Leu Lys Arg Leu 3475 3480 3485 Glu Ser Ser Gly AspVal Pro Ala Gln Arg Ser Gly Asp Thr Arg Ala 3490 3495 3500 Arg Arg SerAsp Val Pro Ala Gln Arg Ser Gly Gly Val Pro Ala Arg 3505 3510 3515 3520Arg Ser Val Asp Val Ser Gly Arg Glu Val Leu Pro Trp Leu Ser Gly 35253530 3535 Gly Ser Val Leu Val Thr Gly Gly Thr Gly Val Leu Gly Ala AlaVal 3540 3545 3550 Ala Arg His Leu Ala Gly Val Cys Gly Val Arg Asp LeuLeu Leu Val 3555 3560 3565 Ser Arg Arg Gly Pro Asp Ala Pro Gly Ala GluGly Leu Arg Ala Glu 3570 3575 3580 Leu Ala Ala Leu Gly Ala Glu Val ArgIle Val Ala Cys Asp Val Gly 3585 3590 3595 3600 Glu Arg Arg Glu Val ValArg Leu Leu Glu Gly Val Pro Ala Gly Cys 3605 3610 3615 Pro Leu Thr GlyVal Val His Ala Ala Gly Val Leu Asp Asp Ala Thr 3620 3625 3630 Ile AlaSer Leu Thr Pro Glu Arg Leu Gly Thr Val Phe Ala Ala Lys 3635 3640 3645Val Asp Ala Ala Leu Leu Leu Asp Glu Leu Thr Arg Gly Met Glu Leu 36503655 3660 Ser Ala Phe Val Leu Phe Ser Ser Ala Ala Gly Ile Leu Gly SerAla 3665 3670 3675 3680 Gly Gln Gly Asn Tyr Ala Ala Ala Asn Ala Ala LeuAsp Ala Leu Ala 3685 3690 3695 Tyr Arg Arg Arg Ala Ala Gly Leu Pro GlyVal Ser Leu Ala Trp Gly 3700 3705 3710 Leu Trp Glu Glu Ala Ser Gly MetThr Gly His Leu Ala Gly Thr Asp 3715 3720 3725 His Arg Arg Ile Ile ArgSer Gly Leu His Pro Met Ser Thr Pro Asp 3730 3735 3740 Ala Leu Ala LeuPhe Asp Ala Ala Leu Ala Leu Asp Arg Pro Val Leu 3745 3750 3755 3760 LeuPro Ala Asp Leu Arg Pro Ala Pro Pro Leu Pro Pro Leu Leu Gln 3765 37703775 Asp Leu Leu Pro Ala Thr Arg Arg Arg Thr Thr Arg Thr Thr Thr Thr3780 3785 3790 Gly Gly Ala Asp Asn Gly Ala Gln Leu His Ala Arg Leu AlaGly Gln 3795 3800 3805 Thr His Glu Gln Gln His Thr Thr Leu Leu Ala LeuVal Arg Ser His 3810 3815 3820 Ile Ala Thr Val Leu Gly His Thr Thr ProAsp Thr Ile Pro Pro Asp 3825 3830 3835 3840 Arg Ala Phe Arg Asp Leu GlyPhe Asp Ser Leu Thr Ala Val Glu Leu 3845 3850 3855 Arg Asn Arg Leu SerArg Thr Thr Gly Leu Arg Leu Pro Thr Thr Leu 3860 3865 3870 Ala Phe AspHis Pro Asn Pro Thr Thr Leu Thr His His Leu His Thr 3875 3880 3885 GlnLeu Gln Pro Gln Pro Asp Asn Ala Val Ala Pro Val Leu Ala Glu 3890 38953900 Leu Asp Lys Leu Glu Ser Ala Leu Ser Ala Leu Asp Lys Thr Asp Ser3905 3910 3915 3920 Ala Ser Glu Arg Val Thr Leu Arg Leu Lys Ser Leu MetLeu Arg Trp 3925 3930 3935 Asn Ala Pro Gln His Pro Thr Ala Glu Ser AlaAsp Asp Asp Glu Lys 3940 3945 3950 Phe Thr Ser Ala Thr Glu Ala Glu IlePhe Lys Phe Ile Asp Asn Asp 3955 3960 3965 Leu Gly Leu Ser 3970 9 32 DNAArtificial Sequence Description of Artificial Sequence primer based onthe sequence between 1954 and 1985 of SEQ ID NO 1 9 accgtggacacggggggctc ggcatcgctc gt 32 10 28 DNA Artificial Sequence Description ofArtificial Sequence antisense primer based on the sequence between 1758and 1776 of SEQ ID NO 1 10 ataagcttaa tcgatccgct gtccggta 28 11 30 DNAArtificial Sequence Description of Artificial Sequence antisense primerbased on the sequence between 2710 and 2729 of SEQ ID NO 1 11 atgaattccctccaaaatca catgcgcatt 30

What is claimed is:
 1. A modified avermectin aglycon synthase comprisingat least one domain with an eliminated or lowered activity, wherein thedomain is selected from the group consisting of acyl carrier protein(ACP), β-ketoacyl ACP synthase (KS), acyltransferase (AT), β-ketoacylACP reductase (KR), dehydratase (DH), enoyl reductase (ER) andthioesterase (TE), which are involved in the synthesizing reaction ofavermectin aglycon.
 2. The modified avermectin aglycon synthaseaccording to claim 1, wherein the modified avermectin aglycon synthaseis derived from Streptomyces avermitilis.
 3. The modified avermectinaglycon synthase according to claim 1, wherein the domain with aneliminated or lowered activity is selected from the group consisting ofATs, ACPs, KS1, AT1, KR1, ACP1, KS2, DH2 and KR2.
 4. A modifiedavermectin aglycon synthase comprising an amino acid sequence whereinone or more amino acid residues are deleted, substituted or added in theamino acid sequence of the avermectin aglycon synthase consisting of theamino acid sequences shown in SEQ ID NOs: 4, 5, 6 and 7, and having anactivity for producing 22,23-dihydroavermectin B1a or a derivativethereof when the modified avermectin aglycon synthase is contacted withan N-acetylcysteamine thioester compound.
 5. The modified avermectinaglycon synthase according to claim 4, which contains a polypeptideconsisting of the amino acid sequence shown in SEQ ID NO:
 8. 6. Themodified avermectin aglycon synthase according to claim 4, wherein theN-acetylcysteamine thioester compound is represented by formula (I):

wherein R¹ and R², which may be the same or different, representhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl or substitutedor unsubstituted heterocycle, or, R¹ and R², combined together, formsubstituted or unsubstituted cycloalkyl.
 7. The modified avermectinaglycon synthase according to claim 6, wherein the N-acetylcysteaminethioester compound is represented by formula (I) in which R¹ is methyland R² is sec-butyl.
 8. A DNA which encodes the modified avermectinaglycon synthase according to any one of claims 1 to
 7. 9. A DNA whichcomprises a DNA encoding a polypeptide consisting of the amino acidsequence shown in SEQ ID NO:
 8. 10. A DNA which comprises a DNAconsisting of the nucleotide sequence shown in SEQ ID NO:
 3. 11. A DNAwhich hybridizes with the DNA according to any one of claims 8 to 10under stringent conditions and encodes a polypeptide having an activityfor producing 22,23-dihydroavermectin B1a or a derivative thereof whenthe modified avermectin aglycom synthase is contacted with theN-acetylcysteamine thioester compound.
 12. A recombinant DNA which isobtained by ligating the DNA according to any one of claims 8 to 11 witha vector.
 13. A transformant which is obtained by introducing therecombinant DNA according to claim 12 into a host cell.
 14. Thetransformant according to claim 13, wherein the host cell is amicroorganism.
 15. The transformant according to claim 14, wherein themicroorganism belongs to the genus Streptomyces.
 16. The transformantaccording to claim 15, wherein the microorganism belonging to the genusStreptomyces is Streptomyces avermitilis.
 17. The transformant accordingto claim 16, which is Streptomyces avermitilis KS1mut.
 18. AnN-acetylcysteamine thioester compound, which is a substrate compound forthe modified avermectin aglycon synthase according to any one of claims1 to 7 and converted to 22,23-dihydroavermectin B1a or a derivativethereof when the compound is contacted with the modified avermectinaglycon synthase.
 19. An N-acetylcysteamine thioester compoundrepresented by formula (I):

wherein R¹ and R² which may be the same or different, representhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl or substitutedor unsubstituted heterocycle, or, R¹ and R², combined together, formsubstituted or unsubstituted cycloalkyl.
 20. The N-acetylcysteaminethioester compound according to claim 19, which is represented byformula (I), wherein R¹ is methyl and R² is sec-butyl.
 21. A process forproducing an N-acetylcysteamine thioester compound which ischaracterized by employing a compound represented by formula (II):

wherein R¹ and R², which may be the same or different, representhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl or substitutedor unsubstituted heterocycle, or, R¹ and R², combined together, formsubstituted or unsubstituted cycloalkyl as a starting material, andincluding a reaction step of adding N-acetylcysteamine.
 22. The processfor producing an N-acetylcysteamine thioester compound according toclaim 21, which is characterized by employing, as a starting material, acompound represented by formula (II):

wherein R¹ and R², which may be the same or different, representhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl or substitutedor unsubstituted heterocycle, or, R¹ and R², combined together, formsubstituted or unsubstituted cycloalkyl, and comprising the steps of:(a) ozone-oxidating the compound, and thereafter adding carbon chains bythe Wittig reaction; (b) deprotecting t-butyldimethylsilyl group of thecompound obtained in step (a) and reintroducing another protecting groupusing chlorotriethylsilane; (c) reducing α-β unsaturated carbon bond ofthe resultant compound in the presence of a palladium-carbon catalyst,hydrolyzing an ester with potassium hydroxide, neutralizing the reactionmixture, and adding N-acetylcysteamine in the presence of a condensingagent to obtain a thioester compound; and (d) removing the protectinggroup by adding acetic acid to the thioester compound.
 23. A process forproducing a modified avermectin aglycon synthase, comprising the stepsof: culturing the transformant according to any one of claims 13 to 17in a medium until a modified polypeptide having an activity of aavermectin aglycon synthase is produced and accumulated in the culture;and collecting the polypeptide from the culture.
 24. A process forproducing 22,23-dihydroavermectin B1a or a derivative thereof,comprising the steps of: contacting a culture of the transformantaccording to any one of claims 13 to 17 or a treated product thereof orthe synthase according to any one of claims 1 to 7 with theN-acetylcysteamine thioester compound according to claim 18 in a medium;and collecting 22,23-dihydroavermectin B1a or a derivative thereofproduced and accumulated in the medium.
 25. A process for producing22,23-dihydroavermectin B1a or a derivative thereof, characterized inthat an N-acetylcysteamine thioester compound is employed as a substratecompound for the modified avermectin aglycon synthase according to anyone of claims 1 to 7.